A benzofive-membered nitrogen heterocyclic compound and its application

Abstract

The present invention relates to a benzopentacyclic nitrogen heterocyclic compound and its application. The benzopentacyclic nitrogen heterocyclic compound has the structure shown in Formula I. The compound can be used as a compound that inhibits the RORγ receptor. This type of compound can effectively inhibit the RORγ protein and has good selectivity for other nuclear receptor family proteins. The benzopentacyclic nitrogen-containing heterocyclic compound or its pharmaceutical composition provided by the present invention can be used to prepare drugs for treating, preventing or improving diseases such as inflammation, autoimmune diseases, cell proliferative disorders, sepsis, cancer, neurodegenerative diseases or viral infections. It has a good inhibitory effect on the treatment of tumors, especially outstanding efficacy for prostate cancer, and also has an improvement effect on the treatment of other diseases.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical medicine, and in particular to a benzofive-membered nitrogen heterocyclic compound and its application. Background Art

[0002] Retinoic acid receptor-related orphan receptor (ROR) is an important class of orphan receptors in the nuclear receptor family. This receptor family includes three members, namely RORα (NR1F1), RORβ (NR1F2) and RORγ (NR1F3), which are distributed in different tissues and organs of the body respectively. RORα is widely expressed in skeletal muscle, liver, lung, skin, adipose tissue, kidney, thymus and brain. The expression site of RORβ is very limited and is only expressed in the central nervous system. There are two subtypes of RORγ, namely RORγ1 and RORγ2, and the latter is also called RORγt. Among them, RORγ1 is highly expressed in skeletal muscle, liver, kidney and adipose tissue. While RORγt is only highly expressed in immune tissues including the thymus.

[0003] TH17 cells are a subset of TH cells that can secrete interleukin 17 (IL-17). As a pro-inflammatory factor, IL-17 plays an important role in the development of inflammation and autoimmune diseases. Therefore, regulating the differentiation of TH17 cells and the secretion of IL-17 can regulate the immune system response. In 2006, Professor Littman of New York University first discovered that RORγ can directly promote the differentiation and development of TH17 cells. RORγ directly regulates the production and secretion levels of IL-17 cytokines and is a key factor in the development of TH17 cells. Therefore, in the treatment of autoimmune diseases, inhibiting RORγ transcription is expected to become a new selection strategy.

[0004] Previous studies have found that the nuclear receptor RORγ is highly expressed in castration-resistant prostate cancer (CRPC), and can act on the upstream of the androgen receptor (AR) gene and regulate the expression of AR and related genes regulated by AR. RORγ inhibitors SR2211 and XY011, XY018 and XY101 obtained by structure-based drug design methods can significantly inhibit the expression of AR and AR-V7, and show good inhibitory effects on cells resistant to the second-generation drug enzalutamide. In addition, RORγ inhibitors also inhibit tumor growth in a mouse xenograft CRPC model. In summary, by inhibiting the target RORγ, the expression of AR gene and downstream signaling pathways can be interfered, which can provide a new treatment method for prostate cancer and its clinical drug resistance. SUMMARY OF THE INVENTION

[0005] In view of the deficiencies of the prior art, one object of the present invention is to provide a benzopentacyclic nitrogen heterocyclic compound. The benzopentacyclic nitrogen heterocyclic compound is a compound as an RORγ receptor inhibitor, and such compounds can effectively inhibit the RORγ protein and have good selectivity for other nuclear receptor family proteins.

[0006] To achieve this object, the present invention adopts the following technical solutions:

[0007] The present invention provides a benzopentacyclic nitrogen heterocyclic compound having the structure shown in Formula I;

[0008]

[0009] In Formula I, X is selected from The wavy line represents the connecting bond of the group;

[0010] In Formula I, Y is selected from CR 5 or an N atom;

[0011] In Formula I, Z is selected from an S atom or NR 10 ;

[0012] In Formula I, R 1 and R 10 each independently selected from 0 to 3 R 11 substituted C1-C10 alkyl, 0 to 3 R 11 substituted C6-C10 aryl, 0 to 3 R 11 substituted C6-C10 aryl C1-C3 alkyl, 0 to 3 R 11 substituted C2-C10 heteroaryl, 0 to 3 R 11 substituted C2-C20 heterocyclic group, 0 to 3 R 11 substituted C2-C10 heteroaryl C1-C3 alkyl, 0 to 3 R 11 substituted C2-20 heterocyclic group C1-C3 alkyl, 0 to 3 R 11 substituted C3-C10 cycloalkyl, 0 to 3 R 11 substituted C3-C10 cycloalkyl C1-C3 alkyl, any one of them;

[0013] The R 11Any one selected from halogen, cyano, nitro, carboxyl, hydroxyl, amino, C1-C10 alkylsulfonyl, C1-C10 alkylsulfonyl substituted with at least one halogen, C1-C10 alkyl ester group, C1-C10 alkyl ester group substituted with at least one halogen, C1-C10 alkyl, C1-C10 alkyl substituted with at least one halogen, C1-C10 alkoxy, C1-C10 alkoxy substituted with at least one halogen, C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with at least one halogen;

[0014] In formula I, the R 2 -R 9 Each independently is selected from hydrogen, halogen, C1-C10 alkyl, C1-C10 alkyl substituted with at least one halogen, C1-C10 alkoxy, C1-C10 alkoxy substituted with at least one halogen, C1-C10 alkylamide group, C1-C10 alkylamide group substituted with at least one halogen, C1-C10 cycloalkylamide group, C1-C10 cycloalkylamide group substituted with at least one halogen, C1-C10 alkylamino group, C1-C10 alkylamino group substituted with at least one halogen, C3-C10 cycloalkylamino group, C3-C10 cycloalkylamino group substituted with at least one halogen.

[0015] The term "substituted" means that one or more hydrogens on one or more specified atoms are replaced by the selection of the indicated group, provided that it does not exceed the normal valence of the specified atom in the existing environment, and the substitution results in a stable compound.

[0016] In the present invention, halogen includes fluorine, chlorine, bromine, and iodine.

[0017] In the present invention, the C2-C20 heterocyclic group refers to a monocyclic heterocyclic group containing 2-10 carbon atoms and a condensed heterocyclic group containing 10-20 carbon atoms. The monocyclic heterocyclic group with 2-10 carbon atoms is a saturated or partially saturated and non-aromatic monocyclic group containing 1-4 heteroatoms (N, O or S). The condensed heterocyclic group with 10-20 carbon atoms is a saturated or partially saturated and non-aromatic cyclic group containing 10-20 carbon atoms and 1-4 heteroatoms (N, O or S) formed by two or more cyclic structures sharing two adjacent atoms with each other. There may be an aromatic ring in the condensed ring, but the condensed ring as a whole does not have aromaticity. Optionally, the ring atoms (such as C, N or S) in the cyclic structure can be oxo-substituted. The C2-C20 monocyclic heterocyclic group includes but is not limited to 2H-aziridinyl, diaziridinyl, azetidinyl, 1,4-dioxanyl, 1,3-dioxolanyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothienyl, 4,5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydrothienyl, tetrahydrofuryl, tetrahydropyridyl, piperidone, tetrahydropyridone, dihydropiperidone, piperazinyl, morpholinyl. The condensed heterocyclic group with 10-20 carbon atoms includes but is not limited to benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuryl, benzopyrrolidinyl, benzimidazolidinyl, benzoxazolidinyl, benzothiazolidinyl, benzisoxazolidinyl, benzisothiazolidinyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, benzotetrahydropyranyl, pyrrolidinyl-fused cyclopropyl, cyclopentyl-fused aziridinyl, pyrrolidinyl-fused cyclobutyl, pyrrolidinyl-fused pyrrolidinyl, pyrrolidinyl-fused piperidinyl, pyrrolidinyl-fused piperazinyl, pyrrolidinyl-fused morpholinyl, piperidinyl-fused morpholinyl, pyridine-fused cyclopentyl, pyridine-fused cyclohexyl, pyridine-fused tetrahydrofuryl, pyridine-fused pyrrolidinyl, pyridine-fused imidazolidinyl, pyridine-fused oxazolidinyl, pyridine-fused thiazolidinyl, pyridine-fused isoxazolidinyl, pyridine-fused isothiazolidinyl, pyridine-fused piperidinyl, pyridine-fused morpholinyl, pyridine-fused piperazinyl, pyridine-fused tetrahydropyranyl, pyrimidine-fused cyclopentyl, pyrimidine-fused cyclohexyl, pyrimidine-fused tetrahydrofuryl, pyrimidine-fused pyrrolidinyl, pyrimidine-fused imidazolidinyl, pyrimidine-fused oxazolidinyl, pyrimidine-fused thiazolidinyl, pyrimidine-fused isoxazolidinyl, pyrimidine-fused isothiazolidinyl, pyrimidine-fused piperidinyl, pyrimidine-fused morpholinyl, pyrimidine-fused piperazinyl, pyrimidine-fused tetrahydropyranyl.

[0018] In the present invention, the C1-C10 alkyl group refers to a branched or unbranched chain alkyl group having 1-10 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, etc.; all carbon atoms can be optionally substituted by one or more halogens.

[0019] In the present invention, the C1-C10 alkoxy group refers to -O-C1-C10 alkyl, where the C1 ~C 10 The alkyl group is as defined above.

[0020] In the present invention, the C1-C10 alkyl amide group refers to -CO-NH-C1-C10 alkyl or C1-C10 alkyl-CO-NH-, and the C1-C10 alkyl group is as defined above.

[0021] In the present invention, the C3-C10 cycloalkyl group refers to a saturated cycloalkane having 3 to 10 carbon atoms; including but not limited to cyclobutyl, cyclopentyl, cyclohexyl, etc. All carbon atoms of the alkyl group are optionally substituted by one or more halogen atoms.

[0022] In the present invention, the C3-C10 cycloalkyl C1-C3 alkyl group refers to a C1-C3 cycloalkyl group linked to a C3-C10 alkyl group, both having the same meaning as defined above. The C6-C10 aryl C1-C3 alkyl group, the C2-C10 heteroaryl C1-C3 alkyl group, and the C2-20 heterocyclic C1-C3 alkyl group all have the same meaning and represent a group formed by the connection of two or three groups.

[0023] In the present invention, the C3-C10 cycloalkyl amide group refers to -CO-NH-C3-C10 cycloalkyl or C3-C10 cycloalkyl-CO-NH-, and the C3-C10 cycloalkyl group is as defined above.

[0024] In the present invention, the C2-C10 heteroaryl group refers to a heteroaryl ring system containing 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from N, O, and S, and including an aromatic 5- or 6-membered monocyclic heteroaryl group and an aromatic 7- to 11-membered heteroaryl bicyclic or fused ring (where at least one of the rings is an aromatic ring). The 5- to 6-membered monocyclic heteroaryl group includes but is not limited to pyridyl, imidazolyl, triazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, and thienyl. The 7- to 11-membered heteroaryl bicyclic or fused ring includes but is not limited to benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, thiophenopyrimidinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuryl, benzopyranyl, benzoxazolyl, benzothiazolyl, pyrrolopyridyl, and imidazopyridyl.

[0025] In the present invention, the C1-C10 alkyl sulfonyl group refers to -SO 2 -C1-C10 alkyl, and the C1-C10 alkyl group is as defined above.

[0026] In the present invention, the C1-C10 alkyl ester group refers to -COO-C1-C10 alkyl, and the C1-C10 alkyl group is as defined above.

[0027] In the present invention, C1-C10 alkylamino refers to -NH-C1-C10 alkyl, and C1-C10 alkyl is as defined above.

[0028] Preferably, the 0-3 R 11 The substituted C2-C20 heterocyclic group is The wavy line represents the bonding site of the group.

[0029] Preferably, R 1 The substituted R in 11 is selected from any one or at least two combinations of C1-C10 alkyl, halogen, trifluoromethoxy, nitro, cyano, carboxyl, methyl ester group, ethyl ester group, amino, methylsulfonyl group, ethylsulfonyl group, preferably any one or at least two combinations of cyano, ethyl ester group, ethylsulfonyl group.

[0030] Preferably, the R 2 -R 5 are all hydrogen.

[0031] Preferably, the R 6 , R 7 , R 8 and R 9 are not all hydrogen at the same time.

[0032] Preferably, the R 6 and R 9 are hydrogen.

[0033] Preferably, the R 7 and R 8 are not all hydrogen at the same time.

[0034] Preferably, among the R 7 and R 8 , only one is hydrogen.

[0035] Preferably, the R 7 and R 8 are each independently selected from any one or at least two combinations of hydrogen, methyl, methoxy, halogen, trifluoromethyl, C2-C10 alkylamide group.

[0036] Preferably, the C2-C10 alkylamide group is isopropylamide group or cyclopentylamide group.

[0037] Preferably, the R 10 is selected from C1-C10 alkyl, cyclobutyl, cyclobutylmethyl, cyclohexylmethyl, pyridylmethyl, phenyl ethyl substituted by 0-3 R 11 , benzyl substituted by 0-3 R 11 in any one.

[0038] Preferably, R 10The substituted R in 11 is selected from any one or at least two combinations of methyl, carboxyl, trifluoromethyl, methyl ester group, halogen, cyano, and methylsulfonyl group.

[0039] Preferably, the benzopentacyclic nitrogen heterocyclic compound has the structure shown in Formula II;

[0040]

[0041] In Formula II, X is selected from

[0042] In Formula II, the R 1 is selected from C1-C10 alkyl substituted by 0-3 R 11 , C6-C10 aryl substituted by 0-3 R 11 , C6-C10 aryl C1-C3 alkyl substituted by 0-3 R 11 , C2-C20 heterocyclic group substituted by 0-3 R 11 (such as ); R 11 is selected from any one of halogen, cyano, nitro, carboxyl, hydroxyl, amino, C1-C10 alkylsulfonyl group, C1-C10 alkylsulfonyl group substituted by at least one halogen, C1-C10 alkyl ester group, C1-C10 alkyl ester group substituted by at least one halogen, C1-C10 alkyl, C1-C10 alkyl substituted by at least one halogen, C1-C10 alkoxy group, and C1-C10 alkoxy group substituted by at least one halogen;

[0043] In Formula II, the R 2 ~R 9 are each independently selected from any one of hydrogen, halogen, C1-C10 alkyl, C1-C10 alkyl substituted by at least one halogen, C1-C10 alkoxy group, and C1-C10 alkoxy group substituted by at least one halogen.

[0044] Preferably, in Formula II, the R 2 is selected from hydrogen or chlorine.

[0045] Preferably, in Formula II, the R 8 is selected from any one of methyl, methoxy, or fluorine.

[0046] Preferably, in Formula II, the R 7 is hydrogen.

[0047] Preferably, the benzopentacyclic nitrogen heterocyclic compound has the structure shown in Formula II-2;

[0048]

[0049] In formula II-2, the R 1 , R 7 and R 8 all have the same selection range as in formula II.

[0050] Preferably, the benzofive-membered nitrogen heterocyclic compound has the structure shown in formula III;

[0051]

[0052] In formula III, Y is selected from CR 5 or an N atom;

[0053] In formula III, R 2 ~R 9 each independently is selected from any one of hydrogen, halogen, C1-C10 alkyl, C1-C10 alkyl substituted with at least one halogen, C1-C10 alkoxy, C1-C10 alkoxy substituted with at least one halogen, C1-C10 alkylamide group, C1-C10 alkylamide group substituted with at least one halogen, C1-C10 cycloalkylamide group, C1-C10 cycloalkylamide group substituted with at least one halogen;

[0054] In formula III, the R 10 is selected from C1-C10 alkyl substituted with 0-3 R 11 , C6-C10 aryl C1-C3 alkyl substituted with 0-3 R 11 , C2-C10 heteroaryl C1-C3 alkyl substituted with 0-3 R 11 (such as pyridylmethylene), C3-C10 cycloalkyl substituted with 0-3 R 11 , C3-C10 cycloalkyl C1-C3 alkyl substituted with 0-3 R 11 ; the R 11 is selected from hydrogen, halogen, cyano, carboxyl, C1-C10 alkyl, C1-C10 alkyl substituted with at least one halogen, C1-C10 alkylsulfonyl, C1-C10 alkylsulfonyl substituted with at least one halogen, C1-C10 alkyl ester group, C1-C10 alkyl ester group substituted with at least one halogen;

[0055] In formula III, the R 12 and R 13 each independently is selected from hydrogen, amino, C1-10 alkyl substituted with 0-3 R 14 , C1-C10 alkylamide group substituted with 0-3 R 14 , or R 12 and R 13 together with the carbon to which they are attached form a C3-C6 carbocycle; the R 14Any one selected from halogen, carboxyl, hydroxyl, amino, C1-C10 alkyl amide group, C1-C10 alkyl amine group, and C1-C10 alkyl ester group.

[0056] Preferably, the R 7 is any one selected from methyl, methoxy, isopropyl amide group or cyclopentyl amide group.

[0057] Preferably, the R 8 is any one selected from methyl, methoxy, trifluoromethyl, isopropyl amide group or cyclopentyl amide group.

[0058] Preferably, the R 12 and R 13 each independently is any one selected from hydrogen, amino or methyl amide group (CH 3 -CO-NH-).

[0059] Preferably, the benzopentacyclic nitrogen heterocyclic compound has the structure shown in Formula III-2;

[0060]

[0061] In Formula III, the Y, R 7 , R 8 , R 10 and R 12 all have the same selection range as in Formula III.

[0062] The second object of the present invention is to provide a pharmaceutically acceptable salt, isomer, racemate, prodrug, co-crystalline complex or solvate of the benzopentacyclic nitrogen heterocyclic compound described in the first object.

[0063] The pharmaceutically acceptable salts of the compounds of the present invention can be synthesized from the compounds of the present invention containing a basic part or an acidic part by conventional chemical methods. Generally, salts of basic compounds are prepared by reacting with appropriate inorganic or organic acids in an appropriate solvent or a combination of solvents. Similarly, salts of acidic compounds are formed by reacting with appropriate inorganic or organic bases. Therefore, the pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by reacting basic compounds of the present invention with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid) or organic acids (such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethanesulfonic acid, trifluoroacetic acid).

[0064] If the compound of the present invention is acidic, it includes salts prepared by pharmaceutically acceptable non-toxic bases, including inorganic bases (including aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganous salts, potassium salts, sodium salts, zinc salts) and organic bases (salts of primary amines, secondary amines and tertiary amines).

[0065] The term "isomers" refers to compounds having the same chemical constitution but different spatial arrangements of atoms or groups. There are mainly diastereomers and enantiomers.

[0066] The term "diastereomers" refers to stereoisomers having two or more asymmetric centers and whose molecules are not mirror images of each other.

[0067] The term "enantiomers" refers to two non-overlapping mirror-image stereoisomers of a compound. An equimolar mixture of two enantiomers is called a "racemic mixture" or "racemate".

[0068] The term "prodrug" includes compounds having moieties that can be metabolized in vivo. Generally, prodrugs are metabolized in vivo to the active drug by esterases or other mechanisms. These prodrugs can be prepared in situ during the final isolation and purification of the compound, or the purified compound can be reacted with a suitable esterifying agent in acid form or with a hydroxyl group respectively.

[0069] A third object of the present invention is to provide an application of the benzopentacyclic nitrogen heterocyclic compound described in the first object or the pharmaceutically acceptable salt, isomer, racemate, prodrug, cocrystal complex or solvate described in the second object in the preparation of an RORγ receptor inhibitor.

[0070] Preferably, the RORγ receptor inhibitor is used for the preparation of a drug for treating cancer, cell proliferative disorder diseases, inflammatory diseases and autoimmune diseases, sepsis, viral infections or neurodegenerative diseases.

[0071] Preferably, the RORγ receptor inhibitor is used for the preparation of a drug for treating cancer.

[0072] Preferably, the RORγ receptor inhibitor is used for the preparation of a drug for treating prostate cancer.

[0073] A fourth object of the present invention is to provide a pharmaceutical composition, and the active ingredient of the pharmaceutical composition includes the benzopentacyclic nitrogen heterocyclic compound described in the first object or the pharmaceutically acceptable salt, isomer, racemate, prodrug, cocrystal complex or solvate described in the second object.

[0074] A fifth object of the present invention is to provide an application of the pharmaceutical composition described in the fourth object in the preparation of a medicament for treating, preventing or improving inflammation, autoimmune diseases, cell proliferative disorder diseases, sepsis, cancer, viral infections or neurodegenerative diseases.

[0075] The drugs prepared from the RORγ receptor inhibitor, and the cancers that can be treated by the drug composition include adrenal tumors, acoustic neuromas, acral melanoma, acral hidradenoma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adipose tissue tumors, adrenocortical carcinoma, adult T-cell leukemia / lymphoma, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, undifferentiated thyroid cancer, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone tumors, brown tumors, Burkitt lymphoma, breast cancer, brain cancer, carcinoma in situ, chondroma, cementoma, myeloid sarcoma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, clear cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colon cancer, small round cell tumors, diffuse large B-cell lymphoma, neuroepithelial tumors, dysgerminoma, embryonal carcinoma endocrine gland tumors, endodermal sinus tumor, esophageal cancer, fibroma, fibrosarcoma, follicular lymphoma, follicular astrocytoma, thyroid cancer gastrointestinal cancer, germ cell tumors, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of bone, glioblastoma, glioblastoma multiforme, glioma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hemangioblastoma, head and neck cancer, hemangiopericytoma malignant tumor, hepatoblastoma, histiocytic lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lethal midline carcinoma, leukemia, Leydig cell tumor of the testis, liposarcoma, lung cancer, lymphangioma, lymphoepithelioma, lymphoma, acute lymphangiosarcoma, lymphocytic leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumors, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, metastatic carcinoma, mixed Mullerian tumors, mucinous tumors, multiple myeloma, muscle tissue tumors, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal cancer, neuroblastoma, neurofibroma, neuroma, ocular cancer, eosinophilic, optic nerve sheath meningioma, tumors, oral cancer, osteosarcoma, ovarian cancer, papillary thyroid cancer, paraganglioma tumors, pineocytoma, pituitary adenoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma,Peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, rectal cancer, sarcoma, seminoma, trophoblastic tumor, skin cancer, small round cell tumor, small cell carcinoma, soft tissue sarcoma, somatostatinoma, spinal cord tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, small intestine cancer, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, thyroid cancer, transitional cell carcinoma, laryngeal cancer, urachal cancer, urogenital cancer, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer or vaginal cancer, etc.

[0076] The drugs prepared from the RORγ receptor inhibitor, and the inflammatory diseases that the drug composition can treat include inflammatory pelvic diseases, urethritis, skin sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, pancreatitis, psoriasis, allergy, Crohn's disease, intestinal syndrome, ulcerative colitis, tissue transplantation rejection, organ transplantation rejection, asthma, allergic rhinitis, chronic obstructive pulmonary disease, autoimmune diseases, alopecia areata, anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, myasthenia gravis, Hashimoto's thyroiditis, allergic dermatitis, degenerative joint diseases, Guillain-Barré syndrome, mycosis fungoides or acute inflammatory response, etc.

[0077] The drugs prepared from the RORγ receptor inhibitor, and the viral infections that the drug composition can treat include human papillomavirus, herpes virus, Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus or hepatitis C virus infection, etc.

[0078] The drugs prepared from the RORγ receptor inhibitor, and the neurodegenerative diseases that the drug composition can treat include Alzheimer's disease, amyotrophic lateral sclerosis, ataxia-telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, multiple sclerosis, Parkinson's disease, primary lateral sclerosis or spinal muscular atrophy, etc.

[0079] The drugs prepared from the RORγ receptor inhibitor, and the drug composition are applicable to various administration routes. Typical but non-limiting examples of the administration routes are: oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal, by lumbar puncture, transurethral, transdermal or parenteral (including intravenous injection, intramuscular injection, subcutaneous, intradermal injection, intraperitoneal, intrathecal, surgical implantation), etc.

[0080] The pharmaceutical composition according to the present invention can be in liquid, semi-liquid or solid form and is formulated in a manner suitable for the intended route of administration. The compositions according to the present invention can be administered by the following routes: oral, parenteral, intraperitoneal, intravenous, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposomal, etc.

[0081] Oral pharmaceutical compositions can be solid, gel or liquid. Examples of solid preparations include, but are not limited to, tablets, capsules, granules and bulk powders. These preparations can optionally contain binders, diluents, disintegrants, lubricants, glidants, sweeteners and flavoring agents, etc. Examples of binders include, but are not limited to, microcrystalline cellulose, glucose solution, gum arabic, gelatin solution, sucrose and starch paste; examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, stearic acid; examples of diluents include, but are not limited to, lactose, sucrose, starch, mannitol, dicalcium phosphate; examples of glidants include, but are not limited to, silica; examples of disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar and carboxymethylcellulose.

[0082] For parenteral administration of the pharmaceutical composition according to the present invention, it is generally by injection, including subcutaneous, intramuscular or intravenous injection. Injectables can be made in any conventional form, such as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in a liquid before injection or emulsions. Examples of pharmaceutically acceptable carriers for the injectables of the present invention include, but are not limited to, aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifying agents, chelating agents and other pharmaceutically acceptable substances. Examples of aqueous carriers include sodium chloride injection, Ringer's injection, isotonic glucose injection, sterile water for injection, glucose and lactated Ringer's injection; examples of non-aqueous carriers include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil; examples of antimicrobial agents include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, etc.; examples of isotonic agents include sodium chloride and glucose; buffers include phosphates and citrates.

[0083] The pharmaceutical composition according to the present invention can also be prepared as a sterile freeze-dried powder for injection. The compound is dissolved in a sodium phosphate buffer solution containing glucose or other suitable excipients, and then the solution is aseptically filtered under standard conditions known to those skilled in the art, followed by freeze-drying to obtain the required preparation.

[0084] Preferably, the cancer includes prostate cancer.

[0085] Compared with the prior art, the present invention has the following beneficial effects:

[0086] The present invention provides a class of compounds with novel structures that can act as RORγ receptor inhibitors. This class of compounds can effectively inhibit the RORγ protein and have good selectivity for other nuclear receptor family proteins. The benzofive-membered nitrogen-containing heterocyclic compounds or their pharmaceutical compositions provided by the present invention can be used to prepare drugs for treating, preventing or improving diseases such as inflammation, autoimmune diseases, cell proliferative disorders, sepsis, cancer, neurodegenerative diseases or viral infections. They have a good inhibitory effect on the treatment of tumors, especially for prostate cancer, with a tumor growth inhibition rate (TGI) of up to 109%. They also have an improvement effect on the treatment of other diseases and have broad application prospects. This class of compounds has stable structures and simple synthesis methods, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0087] Figure 1 It shows the inhibitory effect on tumors of Example 68 in the 22Rv1 mouse xenograft tumor model in Test Example 5.

[0088] Figure 2 It is a graph of the change in the body weight of mice during the medication period of Example 68 in Test Example 5. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0089] For ease of understanding the present invention, the following examples are listed. Those skilled in the art should understand that the examples are only for helping to understand the present invention and should not be regarded as specific limitations on the present invention.

[0090] The meanings represented by the English or English abbreviations involved in the following detailed embodiments are as follows:

[0091] Polyphosphoric acid (PPA); 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); N,N-diisopropylethylamine (DIPEA); dichloromethane (DCM); 1-hydroxybenzotriazole (HOBT); 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI); dimethyl sulfoxide (DMSO).

[0092] The present invention provides representative synthetic routes for compounds of Formula II and Formula III. Benzothiazole compounds have the structure shown in Formula II, and the preparation methods include Route 1 and Route 2; benzimidazole compounds have the structure shown in Formula III, and the preparation methods include Route 3 and Route 4.

[0093] Route 1 is specifically as follows:

[0094]

[0095] The reagents added and reaction conditions in each step are as follows: (a) KOH, H2 O, reflux, overnight; (b): PPA, 4-aminobenzoic acid or 4-amino-2-chlorobenzoic acid, 220 °C, 4 h; (c): R 1 SO 2 Cl, pyridine, 80 °C, overnight; (d): R 1 COOH, HATU, DIPEA, DCM, room temperature, overnight; (e): NaOH, CH 3 OH, room temperature, overnight.

[0096] Route two is specifically as follows:

[0097]

[0098] The reagents added and reaction conditions in each step are as follows: (a) pyridine, 40 °C, 1 hour; (b) Lawesson's reagent, 1,4-dioxane, 110 °C, 3 hours; (c) NaOH, EtOH, potassium ferricyanide, 90 °C, 30 minutes; (d) Pd / C, H 2 , 5 hours, room temperature; e) HATU, DIPEA, DCM, room temperature, overnight.

[0099] Route three is specifically as follows:

[0100]

[0101] The reagents added and reaction conditions in each step are as follows: (a) R 4 NH 2 , DIPEA, DMSO, 95 °C, overnight; or R 4 NH 2 , K 2 CO 3 , DMF, 95 °C, 1 hour; (b) Fe, AcOH, NH 4 Cl, H 2 O, 80 °C, 1 hour; (c) 4-nitrobenzaldehyde, oxone, DMF, room temperature, 1 hour; (d) 2-(4-(ethylsulfonyl)phenyl)acetic acid, HATU, DIPEA, DCM, room temperature, overnight; or 2-(4-(ethylsulfonyl)phenyl)acetic acid, HOBT, EDCI, DIPEA, DCM, room temperature, overnight. (e) NaOH, CH 3 OH, room temperature, overnight.

[0102] Route four is specifically as follows:

[0103]

[0104] The reagents added and reaction conditions in each step are as follows: (a) 5-nitro-2-pyridinecarboxylic acid or 2-((tert-butoxycarbonyl)amino)-2-(4-(ethylsulfonyl)phenyl)acetic acid, HATU, DIPEA, DCM, room temperature, overnight; (b) acetic acid, 120 °C, 4.5 h; (c) Fe, AcOH, ammonium chloride, H 2 O, 80 °C, 1 hour; (d) trifluoroacetic acid (TFA), DCM, room temperature, 3 hours; (e) Ac 2 O, DCM, Et 3 N, room temperature, 3 hours.

[0105] The above preparation method is for illustrative purposes and is not intended to limit the listed compounds or any specific substituents. The number of substituents shown in the scheme does not necessarily conform to the number used in the claims, and for clarity, a single substituent is shown attached to a compound that allows for multiple substituents under the definitions of Formulas II and III above. All compounds encompassed by General Formula I can be obtained by varying the number and position of the substituents.

[0106] Example 1 4-Methyl-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide

[0107] Step 1. Synthesis of 2-amino-5-methylbenzenethiol

[0108]

[0109] Suspend 6-methylbenzo[d]thiazol-2-amine (5 g, 30.5 mmol) in an aqueous solution of KOH (25 g, 44.6 mmol) in water (50 mL), heat under reflux overnight, and monitor the reaction by TLC. After the reaction is complete, cool to ambient temperature and adjust the pH of the solution to 6 with acetic acid. Filter to collect the thick precipitate and wash with water. Partition the residue between dichloromethane and water, wash the organic layer with brine, and dry over anhydrous Na 2 SO 4 and concentrate in vacuo to obtain the target compound as a yellow solid (3.4 g, yield: 80%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.91 (dd, J = 8.2, 1.7 Hz, 1H), 6.81 (d, J = 1.4 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 5.21 (s, 2H), 2.05 (s, 3H).

[0110] Step 2. Synthesis of 4-(6-methylbenzo[d]thiazol-2-yl)aniline

[0111]

[0112] Polyphosphoric acid (20 g) was added to a mixture of 2-amino-5-methylbenzenethiol (2.03 g, 14.58 mmol) and 4-aminobenzoic acid (1.99 g, 14.51 mmol), and the mixture was heated at 220 °C for 4 h. The reaction was monitored by TLC. After the reaction was completed, it was cooled to ambient temperature, and the reaction mixture was slowly poured into ice-cold aqueous sodium carbonate solution (10% w / v), and stirred until the evolution of gas ceased. The precipitated product was collected by filtration, washed with water, and the residue was partitioned between ethyl acetate and water for extraction. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by silica gel column chromatography (PE:EA = 4:1, v / v) to give the target compound as a brown solid (3.14 g, yield: 90%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.80 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 8.6 Hz, 2H), 7.26 (dd, J = 8.3, 1.1 Hz, 1H), 6.65 (d, J = 8.6 Hz, 2H), 5.85 (s, 2H), 2.42 (s, 3H).

[0113] Step 3. Synthesis of 4-methyl-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide (4a)

[0114]

[0115] Compound 4-(6-methylbenzo[d]thiazol-2-yl)aniline (73 mg, 0.3 mmol) and 4-methylbenzenesulfonyl chloride (85.8 mg, 0.45 mmol) were dissolved in 10 mL of pyridine, and the reaction was carried out at 80 °C for 4 h. The reaction was monitored by TLC. After the reaction was completed, it was cooled to room temperature, 30 mL of dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times (50 mL × 3). The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA = 4:1 v / v) to give the target compound as a white solid (37 mg, yield: 31%). 1 H NMR (500 MHz, DMSO-d 6)δ10.71(s,1H),7.93(d,J=8.7Hz,2H),7.90–7.85(m,2H),7.72(d,J=8.3Hz,2H),7.37(d,J=8.2Hz,2H),7.32(dd,J=8.4,1.1Hz,1H),7.27(d,J=8.7Hz,2H),2.43(s,3H),2.32(s,3H).MS(ESI),m / z forC 21 H 18 N 2 O 2 S 2 ([M+H] + ):Calcd 394.51,found 395.0.

[0116] Example 2 4-(tert-Butyl)-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide

[0117]

[0118] Synthesis method was the same as in Example 1, white solid, yield: 79%. 1 H NMR(400MHz,DMSO-d 6 )δ10.75(s,1H),7.94(d,J=8.7Hz,2H),7.90–7.84(m,2H),7.78(d,J=8.5Hz,2H),7.60(d,J=8.6Hz,2H),7.35–7.26(m,3H),2.44(s,3H),1.25(s,9H).MS(ESI),m / z for C 24 H 24 N 2 O 2 S 2 ([M+H] + ):Calcd 436.59,found 437.2.

[0119] Example 3 4-Fluoro-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide

[0120]

[0121] Synthesis method was the same as in Example 1, white solid, yield: 61%. 1 H NMR(400MHz,DMSO-d 6)δ10.76(s,1H),7.95(d,J=8.7Hz,2H),7.92–7.86(m,4H),7.42(t,J=8.8Hz,2H),7.33(dd,8.4,0.8Hz,1H),7.28(d,J=8.7Hz,2H),2.44(s,3H).MS(ESI),m / z for C 20 H 15 FN 2 O 2 S 2 ([M+H] + ):Calcd 398.47,found 398.9.

[0122] Example 4 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-4-(trifluoromethoxy)benzenesulfonamide

[0123]

[0124] The synthesis method was as in Example 1, white solid, yield: 74%. 1 H NMR(400MHz,DMSO-d 6 )δ10.87(s,1H),8.00–7.92(m,4H),7.91–7.85(m,2H),7.58(d,J=8.3Hz,2H),7.33(d,J=8.5Hz,1H),7.29(d,J=8.7Hz,2H),2.44(s,3H).MS(ESI),m / z for C 21 H 15 F 3 N 2 O 3 S 2 ([M+H] + ):Calcd464.48,found 465.0.

[0125] Example 5 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-4-nitrobenzenesulfonamide

[0126]

[0127] The synthesis method was as in Example 1, white solid, yield: 50%. 1 H NMR(400MHz,DMSO-d 6)δ 11.04 (s, 1H), 8.39 (d, J = 8.9 Hz, 2H), 8.07 (d, J = 8.9 Hz, 2H), 7.97 (d, J = 8.7 Hz, 2H), 7.91–7.85 (m, 2H), 7.36–7.27 (m, 3H), 2.44 (s, 3H). MS(ESI), m / z for C 20 H 15 N 3 O 4 S 2 ([M + H] + ): Calcd 425.48, found 426.0.

[0128] Example 6 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-3-nitrobenzenesulfonamide

[0129]

[0130] The synthesis method is as in Example 1, white solid, yield: 38%. 1 H NMR(400 MHz, DMSO-d 6 )δ 11.01 (s, 1H), 8.58–8.54 (m, 1H), 8.46 (dd, J = 8.2, 1.6 Hz, 1H), 8.21 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 8.6 Hz, 2H), 7.91–7.85 (m, 3H), 7.36–7.27 (m, 3H), 2.44 (s, 3H). MS(ESI), m / z for C 20 H 15 N 3 O 4 S 2 ([M + H] + ): Calcd 425.48, found 426.0.

[0131] Example 7 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-nitrobenzenesulfonamide

[0132]

[0133] The synthesis method is as in Example 1, white solid, yield: 54%. 1 H NMR(400 MHz, DMSO-d 6)δ11.16(s,1H),8.07–8.03(m,1H),8.03–7.95(m,3H),7.91–7.81(m,4H),7.36–7.32(m,1H),7.30(d,J=8.7Hz,2H),2.44(s,3H).MS(ESI),m / z for C 20 H 15 N 3 O 4 S 2 ([M+H] + ):Calcd 425.48,found426.0.

[0134] Example 8 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-3-(methylsulfonyl)benzenesulfonamide

[0135]

[0136] The synthesis method is as in Example 1, white solid, yield: 34%. 1 HNMR(400MHz,DMSO-d 6 )δ10.93(s,1H),8.32(s,1H),8.20(d,J=7.7Hz,1H),8.12(d,J=8.0Hz,1H),7.96(d,J=8.6Hz,2H),7.92–7.84(m,3H),7.33(d,J=8.8Hz,1H),7.29(d,J=8.6Hz,2H),3.28(s,3H),2.44(s,3H).MS(ESI),m / z for C 21 H 18 N 2 O 4 S 3 ([M+H] + ):Calcd458.57,found 459.2.

[0137] Example 9 2,4-difluoro-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide

[0138]

[0139] The synthesis method is as in Example 1, white solid, yield: 73%. 1 H NMR(400MHz,DMSO-d 6)δ11.13(s,1H),8.03–7.92(m,3H),7.90–7.85(m,2H),7.58–7.50(m,1H),7.36–7.24(m,4H),2.44(s,3H).MS(ESI),m / z for C 20 H 14 F 2 N 2 O 2 S 2 ([M+H] + ):Calcd 416.46,found 417.1.

[0140] Example 10 2,4,6-Trimethyl-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide

[0141]

[0142] The synthesis method is as in Example 1, white solid, yield: 72%. 1 H NMR(400MHz,DMSO-d 6 )δ10.69(s,1H),7.92(d,J = 8.7Hz,2H),7.89–7.83(m,2H),7.32(dd,J = 8.4,0.8Hz,1H),7.13(d,J = 8.7Hz,2H),7.03(s,2H),2.61(s,6H),2.43(s,3H),2.21(s,3H).MS(ESI),m / z forC 23 H 22 N 2 O 2 S 2 ([M-H] - ):Calcd 422.56,found 421.2.

[0143] Example 11 1-Ethyl N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide

[0144]

[0145] The synthesis method is as in Example 1, white solid, yield: 19%. 1 H NMR(500MHz,DMSO-d 6)δ 11.06 (s, 1H), 8.74 (d, J = 8.4 Hz, 1H), 8.26 (d, J = 7.7 Hz, 1H), 8.13 (d, J = 7.0 Hz, 1H), 8.00–7.93 (m, 1H), 7.90–7.81 (m, 4H), 7.32–7.28 (m, 2H), 7.24 (d, J = 8.8 Hz, 2H), 3.88 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H). MS(ESI), m / z for C 27 H 21 N 3 O 3 S 2 ([M + H] + ): Calcd 499.60, found 500.02.

[0146] Example 12 N-(4-(6-Methylbenzo[d]thiazol-2-yl)phenyl)-1-(p-tolyl)methanesulfonamide

[0147]

[0148] The synthesis method is as in Example 1, white solid, yield: 31%. 1 H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 8.01 (d, J = 8.7 Hz, 2H), 7.94–7.87 (m, 2H), 7.38–7.30 (m, 3H), 7.20–7.09 (m, 4H), 4.51 (s, 2H), 2.46 (s, 3H), 2.28 (s, 3H). MS(ESI), m / z for C 22 H 20 N 2 O 2 S 2 ([M + H] + ): Calcd 408.53, found 409.0.

[0149] Example 13 1-(4-Fluorophenyl)-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)methanesulfonamide

[0150]

[0151] The synthesis method is as in Example 1, white solid, yield: 26%. 1 H NMR(400 MHz, DMSO-d 6)δ 10.26 (s, 1H), 8.01 (d, J = 8.7 Hz, 2H), 7.94–7.87 (m, 2H), 7.38–7.27 (m, 5H), 7.19 (t, J = 8.9 Hz, 2H), 4.60 (s, 2H), 2.46 (s, 3H). MS(ESI), m / z for C 21 H 17 FN 2 O 2 S 2 ([M–1] – ): Calcd 412.50, found 411.1.

[0152] Example 14 N-(4-(6-Methylbenzo[d]thiazol-2-yl)phenyl)-1-(4-(trifluoromethyl)phenyl)methanesulfonamide

[0153]

[0154] The synthesis method is as in Example 1, white solid, yield: 47%. 1 1H NMR (500 MHz, DMSO-d 6 )δ 10.34 (s, 1H), 8.01 (d, J = 8.7 Hz, 2H), 7.94–7.88 (m, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.38–7.30 (m, 3H), 4.75 (s, 2H), 2.46 (s, 3H). MS(ESI), m / z for C 22 H 17 F 3 N 2 O 2 S 2 ([M+H] + ): Calcd 462.51, found 463.0.

[0155] Example 15 N-(4-(6-Methylbenzo[d]thiazol-2-yl)phenyl)-1-(4-nitrophenyl)methanesulfonamide

[0156]

[0157] The synthesis method is as in Example 1, white solid, yield: 40%. 1 1H NMR (400 MHz, DMSO-d 6)δ10.36(s,1H),8.22(d,J = 8.7Hz,2H),8.02(d,J = 8.6Hz,2H),7.94–7.88(m,2H),7.57(d,J = 8.7Hz,2H),7.38–7.31(m,3H),4.81(s,2H),2.46(s,3H).MS(ESI),m / z for C 21 H 17 N 3 O 4 S 2 ([M + H] + ):Calcd 439.50,found 440.0.

[0158] Example 16 1-(4-Cyanophenyl)-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)methanesulfonamide

[0159]

[0160] The synthesis method is as in Example 1, white solid, yield: 22%. 1 H NMR(500MHz,DMSO-d 6 )δ10.36(s,1H),8.02(d,J = 8.7Hz,2H),7.94–7.88(m,2H),7.85(d,J = 8.2Hz,2H),7.48(d,J = 8.2Hz,2H),7.38–7.30(m,3H),4.75(s,2H),2.46(s,3H).MS(ESI),m / z for C 22 H 17 N 3 O 2 S 2 ([M + H] + ):Calcd 419.52,found 420.0.

[0161] Example 17 N-(4-(6-Methylbenzo[d]thiazol-2-yl)phenyl)-1-(4-(methylsulfonyl)phenyl)methanesulfonamide

[0162]

[0163] The synthesis method is as in Example 1, white solid, yield: 60%. 1 H NMR(400MHz,DMSO-d 6)δ10.37(s,1H),8.02(d,J=8.7Hz,2H),7.94–7.88(m,4H),7.56(d,J=8.3Hz,2H),7.39–7.30(m,3H),4.76(s,2H),3.20(s,3H),2.46(s,3H).MS(ESI),m / z for C 22 H 20 N 2 O 4 S 3 ([M+H] + ):Calcd472.59,found 472.9.

[0164] Example 18 Methyl 4-((N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)sulfamoyl)methyl)benzoate

[0165]

[0166] The synthesis method was the same as that in Example 1, white solid, yield: 30%. 1 H NMR(500MHz,DMSO-d 6 )δ10.33(s,1H),8.01(d,J=8.6Hz,2H),7.95–7.89(m,4H),7.43(d,J=8.2Hz,2H),7.37–7.30(m,3H),4.71(s,2H),3.83(s,3H),2.46(s,3H).MS(ESI),m / z for C 23 H 20 N 2 O 4 S 2 ([M+H] + ):Calcd452.54,found 453.0.

[0167] Example 19 4-((N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)sulfamoyl)methyl)benzoic acid

[0168]

[0169] Dissolve Example 18 (40 mg, 0.09 mmol) in 5 mL of methanol, add 10 mL of 2 M NaOH, and stir at room temperature for 2 h. After the reaction is completed, rotate off the methanol under reduced pressure, adjust the pH to 5-6 with 1 M dilute hydrochloric acid, filter the precipitated solid by suction to obtain the target compound as a white solid (28.8 mg, yield: 73%) 1 H NMR(500MHz,DMSO-d 6)δ 10.38 (s, 1H), 8.23 (d, J = 8.7 Hz, 2H), 8.02 (d, J = 8.7 Hz, 2H), 7.94–7.88 (m, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.38–7.31 (m, 3H), 4.82 (s, 2H), 2.46 (s, 3H). MS(ESI), m / z for C 22 H 18 N 2 O 4 S 2 ([M+H] + ): Calcd 438.52, found 440.0. MS(ESI), m / z for C 23 H 20 N 2 O 4 S 2 ([M+H] + ): Calcd 452.54, found 453.0.

[0170] Example 20 4-((N-(4-(6-Methylbenzo[d]thiazol-2-yl)phenyl)sulfamoyl)methyl)phenyl propionate

[0171]

[0172] The synthesis method was as in Example 1, white solid, yield: 55%. 1 HNMR(400 MHz, DMSO-d 6 )δ 10.30 (s, 1H), 8.01 (d, J = 8.7 Hz, 2H), 7.95–7.87 (m, 4H), 7.42 (d, J = 8.2 Hz, 2H), 7.38–7.29 (m, 3H), 4.70 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.46 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H). MS(ESI), m / z for C 24 H 22 N 2 O 4 S 2 ([M+H] + ): Calcd 466.57, found 467.1.

[0173] Example 21 N-(4-(6-Methylbenzo[d]thiazol-2-yl)phenyl)-1-(3-nitrophenyl)methanesulfonamide

[0174]

[0175] The synthesis method was as in Example 1, a white solid, yield: 55%. 1 HNMR(400MHz,DMSO-d 6 )δ10.33(s,1H),8.21(d,J=8.2Hz,1H),8.16(s,1H),8.00(d,J=8.7Hz,2H),7.94–7.88(m,2H),7.74(d,J=7.7Hz,1H),7.67(t,J=7.8Hz,1H),7.38–7.29(m,3H),4.83(s,2H),2.46(s,3H).MS(ESI),m / z for C 21 H 17 N 3 O 4 S 2 ([M-H] - ):Calcd439.50,found 438.0.

[0176] Example 22 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-1-(2-nitrophenyl)methanesulfonamide

[0177]

[0178] The synthesis method was as in Example 1, a white solid, yield: 20%. 1 H NMR(400MHz,DMSO-d 6 )δ10.47(s,1H),8.04(d,J=8.1Hz,1H),8.00(d,J=8.6Hz,2H),7.94–7.89(m,2H),7.73(td,J=7.6,0.7Hz,1H),7.64(t,J=7.5,Hz,1H),7.50(d,J=7.0Hz,1H),7.35(dd,J=8.5,0.8Hz,1H),7.28(d,J=8.7Hz,2H),5.05(s,2H),2.46(s,3H).MS(ESI),m / z for C 21 H 17 N 3 O 4 S 2 ([M+H] + ):Calcd 439.50,found 440.0.

[0179] Example 23 Methyl 3-((N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)sulfamoyl)methyl)benzoate

[0180]

[0181] The synthesis method was as in Example 1, a white solid, yield: 25%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.27 (s, 1H), 8.00 (d, J = 8.6 Hz, 2H), 7.95–7.86 (m, 4H), 7.58–7.48 (m, 2H), 7.37–7.28 (m, 3H), 4.71 (s, 2H), 3.83 (s, 3H), 2.46 (s, 3H). MS (ESI), m / z for C 23 H 20 N 2 O 4 S 2 ([M+H] + ): Calcd 452.54, found 453.0.

[0182] Example 24 1-(3-Aminophenyl)-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)methanesulfonamide

[0183]

[0184] Example 21 (50 mg, 0.11 mmol) and 10% palladium on carbon (about 55% water content) (100 mg) were added to MeOH (10 mL) as a solvent, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After completion, the mixture was filtered by suction using diatomaceous earth as a filter aid, and the filtrate was concentrated to obtain a crude product, which was separated by silica gel column chromatography (PE:EA = 4:1, v / v) to obtain the target compound as a white solid (13 mg, yield: 29%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.24 (s, 1H), 8.15–7.78 (m, 4H), 7.47–7.21 (m, 3H), 7.09–6.85 (m, 1H), 6.62–6.45 (m, 2H), 6.44–6.25 (m, 1H), 5.11 (s, 2H), 4.35 (s, 2H), 2.45 (s, 3H). MS (ESI), m / z for C 21 H 19 N 3 O 2 S 2 ([M+H] + ): Calcd 409.52, found 410.0.

[0185] Example 25 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)acetamide

[0186]

[0187] Dissolve compound 4-(6-methylbenzo[d]thiazol-2-yl)aniline (80 mg, 0.33 mmol), diisopropylethylamine (127.7 mg, 0.99 mmol) and HATU (188.1 mg, 0.495 mmol) in 10 mL of DCM. Stir the reaction mixture for 15 minutes, then add compound 2-(4-(ethylsulfonyl)phenyl)acetic acid (112.86 mg, 0.495 mmol), and stir the resulting mixture overnight at room temperature. After the reaction is completed, dilute with water and extract with dichloromethane (20 mL × 3). Dry the combined organic layers with anhydrous Na 2 SO 4 and concentrate under reduced pressure. The crude product is separated by silica gel column chromatography (PE:EA = 3:1 v / v) to obtain the target compound as a white solid (70 mg, yield: 47%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.56 (s, 1H), 8.02 (d, J = 8.7 Hz, 2H), 7.92–7.83 (m, 4H), 7.79 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.4 Hz, 1H), 3.86 (s, 2H), 3.32–3.23 (m, 2H), 2.45 (s, 3H), 1.10 (t, J = 7.3 Hz, 3H). MS (ESI), m / z for C 24 H 22 N 2 O 3 S 2 ([M+H] + ): Calcd 450.57, found 451.1.

[0188] Example 26 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)heptanamide

[0189]

[0190] The synthesis method is as in Example 25, white solid, yield: 39%. 1 H NMR (400 MHz, DMSO-d 6)δ10.16(s,1H),8.00(d,J=8.7Hz,2H),7.92–7.86(m,2H),7.78(d,J=8.7Hz,2H),7.34(d,J=8.4Hz,1H),2.45(s,3H),2.35(t,J=7.4Hz,2H),1.67–1.55(m,2H),1.35–1.25(m,6H),0.87(t,J=6.7Hz,3H).MS(ESI),m / z for C 21 H 24 N 2 OS([M+H] + ):Calcd 352.50,found 353.1.

[0191] Example 27 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(p-tolyl)acetamide

[0192]

[0193] The synthesis method was as in Example 25, white solid, yield: 23%. 1 H NMR(400MHz,DMSO-d 6 )δ10.44(s,1H),8.01(d,J=8.7Hz,2H),7.93–7.85(m,2H),7.78(d,J=8.7Hz,2H),7.34(d,J=8.8Hz,1H),7.23(d,J=7.9Hz,2H),7.14(d,J=7.8Hz,2H),3.63(s,2H),2.45(s,3H),2.28(s,3H).MS(ESI),m / z for C 23 H 20 N 2 OS([M+H] + ):Calcd372.49,found 373.0.

[0194] Example 28 N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(2-nitrophenyl)acetamide

[0195]

[0196] The synthesis method was as in Example 25, white solid, yield: 35%. 1 H NMR(400MHz,DMSO-d 6)δ 10.55 (s, 1H), 8.08 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 8.7 Hz, 2H), 7.93–7.86 (m, 2H), 7.78–7.70 (m, 3H), 7.62–7.55 (m, 2H), 7.34 (d, J = 8.8 Hz, 1H), 4.19 (s, 2H), 2.45 (s, 3H). MS(ESI), m / z for C 22 H 17 N 3 O 3 S([M + H] + ): Calcd 403.46, found 404.3.

[0197] Example 29 N-(3-chloro-4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

[0198]

[0199] The synthesis method was as in Example 25, white solid. Yield: 42%. 1 H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.05 (d, J = 1.8 Hz, 1H), 7.99–7.93 (m, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.66 (dd, J = 8.9, 1.9 Hz, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.39 (dd, J = 8.4, 0.8 Hz, 1H), 3.88 (s, 2H), 3.28 (q, J = 7.6 Hz, 2H), 2.47 (s, 3H), 1.10 (t, J = 7.4 Hz, 3H). MS(ESI), m / z for C 24 H 21 ClN 2 O 3 S 2 ([M + H] + ): Calcd 485.01, found 485.0.

[0200] Example 30 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-fluorobenzo[d]thiazol-2-yl)phenyl)acetamide

[0201] Step 1, Synthesis of N-(4-fluorophenyl)-4-nitrobenzamide

[0202]

[0203] Dissolve 4-fluoroaniline (2 g, 18.0 mmol) in pyridine (10 mL), and then slowly add 4-nitrobenzoyl chloride (4.0 g, 21.6 mmol). React at 40 °C for 1 hour. Monitor the reaction by TLC. After the reaction is completed, cool it to room temperature, add 50 mL of dilute hydrochloric acid to the reaction mixture, extract with ethyl acetate three times (50 mL × 3), combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by silica gel column chromatography (PE:EA = 4:1 v / v) to obtain the target compound as a white solid (3.58 g, yield: 76%). 1 H NMR(400MHz,DMSO-d 6 )δ10.60(s,1H),8.37(d,J=8.8Hz,2H),8.18(d,J=8.8Hz,2H),7.88–7.70(m,2H),7.22(t,J=8.9Hz,2H).

[0204] Step 2. Synthesis of N-(4-fluorophenyl)-4-nitrobenzothioamide

[0205]

[0206] Add N-(4-fluorophenyl)-4-nitrobenzamide (3.58 g, 13.76 mmol) and Lawesson's reagent (2.78 g, 6.88 mmol) to 1,4-dioxane (20 mL) as the solvent. Heat the mixture to 110 °C and continue stirring for 3 h. After completion, cool the reaction system to room temperature and concentrate under reduced pressure. Then add water, and filter the precipitated solid by suction. Wash the filter cake with water and dry it. Recrystallize from methanol to obtain the target compound as an orange solid (2.74 g, yield: 72%). 1 H NMR(400MHz,DMSO-d 6 )δ12.16(s,1H),8.29(d,J=8.7Hz,2H),8.01(d,J=8.6Hz,2H),7.94–7.80(m,2H),7.29(t,J=8.8Hz,2H).

[0207] Step 3. Synthesis of 6-fluoro-2-(4-nitrophenyl)benzothiazole

[0208]

[0209] N-(4-Fluorophenyl)-4-nitrobenzenemethanethioamide (2.0 g, 7.24 mmol) was dissolved in an aqueous sodium hydroxide solution (2.9 g, 72.4 mmol) (containing 3 ml of ethanol and 30 ml of water), and then an aqueous solution (20 ml) of potassium ferricyanide (9.54 g, 28.98 mmol) was added dropwise to this solution. The mixture was stirred at 90 °C for 30 minutes. After completion, the reaction system was cooled to room temperature, and a precipitate formed. The precipitated solid was filtered by suction. The filter cake was washed with water and dried, and recrystallized (EA:PE = 1:2, v / v) to obtain the target compound as a yellow solid (1.6 g, yield: 81%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.38 (d, J = 8.8 Hz, 2H), 8.32 (d, J = 8.8 Hz, 2H), 8.20–8.11 (m, 2H), 7.47 (td, J = 9.1, 2.5 Hz, 1H).

[0210] Step 4. Synthesis of 4-(6-Fluorobenzo[d]thiazol-2-yl)aniline

[0211]

[0212] Compound 6-fluoro-2-(4-nitrophenyl)benzo[d]thiazole (0.8 g, 2.92 mmol) and 10% palladium on carbon (about 55% water content) (160 mg) were added to a solvent of MeOH (10 mL), and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. After completion, the mixture was filtered by suction using diatomaceous earth as a filter aid, and the filtrate was concentrated to obtain a crude product, which was separated by silica gel column chromatography (PE:EA = 4:1, v / v) to obtain the target compound as a white solid (0.5 g, yield: 70%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.00–7.85 (m, 2H), 7.73 (d, J = 8.5 Hz, 2H), 7.30 (td, J = 9.0, 2.5 Hz, 1H), 6.67 (d, J = 8.5 Hz, 2H), 5.88 (s, 2H).

[0213] Step 5. Synthesis of 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-fluorobenzo[d]thiazol-2-yl)phenyl)acetamide

[0214]

[0215] The synthesis method was as in Example 25, white solid, yield: 56%. 1 H NMR (400 MHz, DMSO-d 6)δ 10.59 (s, 1H), 8.07–7.98 (m, 4H), 7.85 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.39 (td, J = 9.1, 2.6 Hz, 1H), 3.86 (s, 2H), 3.27 (q, J = 7.2 Hz, 2H), 1.10 (t, J = 7.3 Hz, 3H). MS(ESI), m / z for C 23 H 19 FN 2 O 3 S 2 ([M+H] + ): Calcd 454.53, found 455.0.

[0216] Example 31 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methoxybenzo[d]thiazol-2-yl)phenyl)acetamide

[0217]

[0218] The synthesis method was as in Example 30, white solid, yield: 56%. 1 H NMR (400 MHz, DMSO-d 6 )δ 10.55 (s, 1H), 7.99 (d, J = 8.7 Hz, 2H), 7.89 (d, J = 8.9 Hz, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 2.5 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.11 (dd, J = 8.9, 2.6 Hz, 1H), 3.85 (s, 2H), 3.84 (s, 3H), 3.27 (q, J = 7.6 Hz, 2H), 1.10 (t, J = 7.3 Hz, 3H). MS(ESI), m / z for C 24 H 22 N 2 O 4 S 2 ([M+Na] + ): Calcd 466.57, found 489.7.

[0219] Example 32 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(4-methylphenethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0220] Step 1. Synthesis of 5-methyl-N-(4-methylphenethyl)-2-nitroaniline

[0221]

[0222] Dissolve 3-fluoro-4-nitrotoluene (2.0 g, 12.9 mmol) in DMSO (5 mL), then add 4-methylphenethylamine (5.23 g, 38.7 mmol) and DIPEA (2.51 g, 19.4 mmol). Stir the reaction mixture at 95 °C overnight. Monitor the reaction by TLC. After completion, add water and extract with ethyl acetate (50 mL × 3). Combine the organic layers, dry over anhydrous Na 2 SO 4 2SO4, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (PE:EA = 50:1 v / v) to obtain the target compound as a yellow solid (2.8 g, yield: 80%). 1 1H NMR (400 MHz, DMSO-d 6 6) δ 8.09 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 6.6 Hz, 1H), 7.12 (d, J = 5.7 Hz, 1H), 6.88 (s, 1H), 6.51 (d, J = 7.9 Hz, 1H), 3.62–3.50 (m, 2H), 2.90 (t, J = 6.8 Hz, 2H), 2.31 (s, 3H), 2.27 (s, 3H).

[0223] Step 2. Synthesis of 5-methyl-N 1 -(4-methylphenethyl)benzene-1,2-diamine

[0224]

[0225] Add iron powder (3.46 g, 61.8 mmol), ammonium chloride (551.1 mg, 10.3 mmol) and acetic acid (1.24 g, 20.6 mmol) to 20 mL of water, and heat to 50 °C and stir for 10 min. Dissolve 5-methyl-N-(4-methylphenethyl)-2-nitroaniline (2.8 g, 10.3 mmol) in 15 mL of DMF, and quickly add it to the above mixed solution. Continue to stir for 1 hour and monitor the reaction by TLC. After completion, cool to room temperature, filter the mixture by suction, adjust the pH of the aqueous layer to 8 - 9 with sodium carbonate solution, then extract with ethyl acetate (50 mL × 3). Combine the organic layers, wash with saturated sodium chloride solution, dry over anhydrous Na 2 SO 4 2SO4, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (PE:EA = 10:1 v / v) to obtain the target compound as a yellow oily liquid (2.1 g, yield: 81%). 1 1H NMR (400 MHz, DMSO-d6 ) δ 7.17 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.9 Hz, 2H), 6.43 (d, J = 7.6 Hz, 1H), 6.28 (s, 1H), 6.22 (d, J = 7.6 Hz, 1H), 4.36 (t, J = 5.5 Hz, 1H), 4.21 (s, 2H), 3.23–3.15 (m, 2H), 2.83 (t, J = 7.4 Hz, 2H), 2.27 (s, 3H), 2.12 (s, 3H).

[0226] Step 3. Synthesis of 6-methyl-1-(4-methylphenethyl)-2-(4-nitrophenyl)-1H-benzo[d]imidazole

[0227]

[0228] 5-Methyl-N 1 -(4-methylphenethyl)benzene-1,2-diamine (1.3 g, 5.4 mmol), 4-nitrobenzaldehyde (816.0 mg, 5.4 mmol) and OXONE (1.84 g, 3.0 mmol) were added to 20 mL of DMF, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After completion, water was added and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated sodium chloride solution and dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 2:1 v / v) to obtain the target compound as a yellow solid (1.78 g, yield: 86%). 1 1H NMR (400 MHz, CDCl 3 ) δ 8.21 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.27 (s, 1H), 7.19 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 7.8 Hz, 2H), 6.64 (d, J = 7.9 Hz, 2H), 4.45 (t, J = 6.8 Hz, 2H), 3.03 (t, J = 6.8 Hz, 2H), 2.57 (s, 3H), 2.29 (s, 3H).

[0229] Step 4. Synthesis of 4-(6-methyl-1-(4-methylphenethyl)-1H-benzo[d]imidazol-2-yl)aniline

[0230]

[0231] Using the intermediate 6-methyl-1-(4-methylphenethyl)-2-(4-nitrophenyl)-1H-benzo[d]imidazole as the raw material. The synthesis method refers to Step 2. Yellow solid, yield: 85%. 1 H NMR(400MHz,DMSO)δ7.46(d,J=8.1Hz,1H),7.36(s,1H),7.28(d,J=8.5Hz,2H),7.04(d,J=7.8Hz,2H),7.00(dd,J=8.3,1.0Hz,1H),6.97(d,J=8.0Hz,2H),6.65(d,J=8.5Hz,2H),5.51(s,2H),4.34(t,J=8.0Hz,2H),2.97(t,J=7.6Hz,2H),2.45(s,3H),2.25(s,3H).

[0232] Step 5: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(4-methylphenethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0233]

[0234] Dissolve the compound 4-(6-methyl-1-(4-methylphenethyl)-1H-benzo[d]imidazol-2-yl)aniline (150 mg, 0.44 mmol), diisopropylethylamine (170.3 mg, 1.32 mmol) and HATU (250.8 mg, 0.66 mmol) in 10 mL of DCM. Stir the reaction mixture for 15 minutes, then add the compound 2-(4-(ethylsulfonyl)phenyl)acetic acid (121.0 mg, 0.53 mmol), and stir the resulting mixture overnight at room temperature. After the reaction is completed, dilute with water and extract with dichloromethane (50 mL×3). Combine the organic layers and dry with anhydrous Na 2 SO 4 Dry, concentrate under reduced pressure. The crude product is separated by silica gel column chromatography (DCM:CH 3 OH = 70:1 v / v) to obtain the target compound as a white solid (70 mg, yield: 29%). 1 H NMR(400MHz,DMSO-d 6)δ 10.47 (s, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 8.7 Hz, 2H), 7.43 (s, 1H), 7.05 (dd, J = 8.2, 0.8 Hz, 1H), 6.98 (d, J = 7.7 Hz, 2H), 6.86 (d, J = 7.9 Hz, 2H), 4.39 (t, J = 7.3 Hz, 2H), 3.86 (s, 2H), 3.28 (q, J = 7.5 Hz, 2H), 2.95 (t, J = 7.3 Hz, 2H), 2.47 (s, 3H), 2.23 (s, 3H), 1.11 (t, J = 7.4 Hz, 3H). MS(ESI), m / z for C 33 H 33 N 3 O 3 S([M-H] - ): Calcd 551.71, found 550.4.

[0235] Example 33 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-propyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0236]

[0237] The synthesis method was as in Example 32, white solid, yield: 45%. 1 HNMR(500 MHz, DMSO-d 6 )δ 10.51 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 1H), 7.42 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 4.21 (t, J = 7.4 Hz, 2H), 3.86 (s, 2H), 3.28 (q, J = 7.5 Hz, 2H), 2.46 (s, 3H), 1.71–1.64 (m, 2H), 1.10 (t, J = 7.4 Hz, 3H), 0.73 (t, J = 7.3 Hz, 3H). MS(ESI), m / z for C 27 H 29 N 3 O 3 S([M+H] + ): Calcd 475.61, found 476.3.

[0238] Example 34 N-(4-(1-Butyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

[0239]

[0240] The synthesis method is as in Example 32, white solid, yield: 26%. 1 HNMR(400MHz,DMSO-d 6 )δ10.53(s,1H),7.87(d,J=8.2Hz,2H),7.80(d,J=8.6Hz,2H),7.71(d,J=8.6Hz,2H),7.64(d,J=8.2Hz,2H),7.53(d,J=8.2Hz,1H),7.45(s,1H),7.08(d,J=8.1Hz,1H),4.26(t,J=7.3Hz,2H),3.86(s,2H),3.33–3.23(m,2H),2.47(s,3H),1.71–1.59(m,2H),1.19–1.07(m,5H),0.76(t,J=7.3Hz,3H).MS(ESI),m / z for C 28 H 31 N 3 O 3 S([M+H] + ):Calcd 489.63,found490.5.

[0241] Example 35 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-pentyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0242]

[0243] The synthesis method is as in Example 32, white solid, yield: 31%. 1 H NMR(400MHz,DMSO-d 6)δ10.50(s,1H),7.86(d,J=8.2Hz,2H),7.79(d,J=8.6Hz,2H),7.70(d,J=8.6Hz,2H),7.64(d,J=8.2Hz,2H),7.52(d,J=8.2Hz,1H),7.41(s,1H),7.06(d,J=8.1Hz,1H),4.24(t,J=7.3Hz,2H),3.86(s,2H),3.28(q,J=7.2Hz,2H),2.46(s,3H),1.70–1.61(m,2H),1.20–1.06(m,7H),0.75(t,J=7.0Hz,3H).MS(ESI),m / z for C 29 H 33 N 3 O 3 S([M+H] + ):Calcd 503.66,found504.7.

[0244] Example 36 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(1-isopropyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0245]

[0246] The synthesis method was as in Example 32, white solid, yield: 28%. 1 H NMR(400MHz,DMSO)δ10.52(s,1H),7.86(d,J=8.2Hz,2H),7.78(d,J=8.5Hz,2H),7.64(d,J=8.2Hz,2H),7.61–7.56(m,3H),7.51(d,J=8.2Hz,1H),7.03(d,J=8.1Hz,1H),4.75–4.63(m,1H),3.86(s,2H),3.28(q,J=7.3Hz,2H),2.46(s,3H),1.57(d,J=6.9Hz,6H),1.11(t,J=7.3Hz,3H).MS(ESI),m / z for C 27 H 29 N 3 O 3 S([M+H] + ):Calcd 475.61,found 476.3.

[0247] Example 37 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(1-isobutyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0248]

[0249] The synthesis method was as in Example 32. It was a white solid with a yield of 27%. 1 H NMR(400MHz,DMSO-d 6 )δ10.54(s,1H),7.87(d,J = 8.2Hz,2H),7.80(d,J = 8.6Hz,2H),7.73(d,J = 8.6Hz,2H),7.64(d,J = 8.2Hz,2H),7.55(d,J = 8.2Hz,1H),7.50(s,1H),7.10(d,J = 8.2Hz,1H),4.16(d,J = 7.5Hz,2H),3.87(s,2H),3.28(q,J = 7.2Hz,2H),2.47(s,3H),2.01–1.87(m,1H),1.11(t,J = 7.3Hz,3H),0.64(d,J = 6.6Hz,6H).MS(ESI),m / z for C 28 H 31 N 3 O 3 S([M + H] + ):Calcd 489.63,found 490.5.

[0250] Example 38 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(1-isopentyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0251]

[0252] The synthesis method was as in Example 32. It was a white solid with a yield of 41%. 1 H NMR(400MHz,DMSO-d 6) δ 10.50 (s, 1H), 7.87 (d, J = 6.9 Hz, 2H), 7.80 (d, J = 7.4 Hz, 2H), 7.70 (d, J = 7.3 Hz, 2H), 7.64 (d, J = 7.0 Hz, 2H), 7.52 (d, J = 7.4 Hz, 1H), 7.39 (s, 1H), 7.05 (d, J = 7.2 Hz, 1H), 4.33–4.16 (m, 2H), 3.87 (s, 2H), 3.32–3.22 (m, 2H), 2.47 (s, 3H), 1.63–1.52 (m, 2H), 1.51–1.41 (m, 1H), 1.11 (t, J = 7.4 Hz, 3H), 0.79 (d, J = 5.0 Hz, 6H). MS(ESI), m / z for C 29 H 33 N 3 O 3 S([M + H] + ): Calcd 503.66, found 504.7.

[0253] Example 39 N-(4-(1-Cyclobutyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

[0254]

[0255] The synthesis method was as in Example 32, white solid, yield: 30%. 1 HNMR(400 MHz, DMSO-d 6 ) δ 10.52 (s, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.5 Hz, 2H), 7.67–7.58 (m, 5H), 7.54 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 5.13–5.01 (m, 1H), 3.87 (s, 2H), 3.28 (q, J = 7.2 Hz, 2H), 2.76–2.61 (m, 2H), 2.49 (s, 3H), 2.43–2.32 (m, 2H), 1.95–1.70 (m, 2H), 1.11 (t, J = 7.3 Hz, 3H). MS(ESI), m / z for C 28 H 29 N 3 O 3 S([M + H] + ): Calcd 487.62, found 488.5.

[0256] Example 40 N-(4-(1-(Cyclobutylmethyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

[0257]

[0258] The synthesis method was as in Example 32. It was a white solid with a yield of 22%. 1 HNMR(400MHz,DMSO-d 6 )δ10.50(s,1H),7.87(d,J=8.1Hz,2H),7.79(d,J=8.5Hz,2H),7.70(d,J=8.5Hz,2H),7.64(d,J=8.1Hz,2H),7.50(d,J=8.2Hz,1H),7.44(s,1H),7.04(d,J=8.2Hz,1H),4.35(d,J=7.2Hz,2H),3.86(s,2H),3.32–3.24(m,2H),2.60–2.51(m,1H),2.46(s,3H),1.78–1.57(m,4H),1.54–1.44(m,2H),1.11(t,J=7.3Hz,3H).MS(ESI),m / z for C 29 H 31 N 3 O 3 S([M+H] + ):Calcd501.65,found 502.5.

[0259] Example 41 N-(4-(1-(Cyclohexylmethyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

[0260]

[0261] The synthesis method was as in Example 32. It was a white solid with a yield of 40%. 1 H NMR(400MHz,DMSO-d 6)δ10.50(s,1H),7.87(d,J=8.2Hz,2H),7.78(d,J=8.6Hz,2H),7.70(d,J=8.5Hz,2H),7.64(d,J=8.1Hz,2H),7.51(d,J=8.1Hz,1H),7.42(s,1H),7.04(d,J=8.2Hz,1H),4.17(d,J=7.2Hz,2H),3.86(s,2H),3.28(q,J=7.2Hz,2H),2.46(s,3H),1.69–1.56(m,1H),1.53–1.42(m,4H),1.34–1.19(m,6H),1.11(t,J=7.6Hz,3H).MS(ESI),m / z for C 31 H 35 N 3 O 3 S([M+H] + ):Calcd 529.70,found 530.7.

[0262] Example 42 N-(4-(1-Benzyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

[0263]

[0264] The synthesis method was as in Example 32, white solid, yield: 20%. 1 H NMR(400MHz,DMSO-d 6 )δ10.48(s,1H),7.85(d,J=8.2Hz,2H),7.72(d,J=8.7Hz,2H),7.66(d,J=8.7Hz,2H),7.64–7.55(m,3H),7.32–7.20(m,4H),7.08(d,J=8.1Hz,1H),6.99(d,J=7.2Hz,2H),5.55(s,2H),3.84(s,2H),3.32–3.22(m,2H),2.39(s,3H),1.10(t,J=7.3Hz,3H).MS(ESI),m / z forC 31 H 29 N 3 O 3 S([M+H] + ):Calcd 523.65,found 524.3.

[0265] Example 43 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(4-methylbenzyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0266]

[0267] The synthesis method was as in Example 32. It was a white solid with a yield of 25%. 1 H NMR(400MHz,DMSO-d 6 )δ10.49(s,1H),7.85(d,J=8.2Hz,2H),7.73(d,J=8.7Hz,2H),7.66(d,J=8.7Hz,2H),7.62(d,J=8.2Hz,2H),7.57(d,J=8.2Hz,1H),7.25(s,1H),7.12–7.03(m,3H),6.88(d,J=7.9Hz,2H),5.49(s,2H),3.84(s,2H),3.27(q,J=7.2Hz,2H),2.39(s,3H),2.22(s,3H),1.10(t,J=7.3Hz,3H).MS(ESI),m / z for C 32 H 31 N 3 O 3 S([[M+H] + ):Calcd 537.68,found 538.6.

[0268] Example 44 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-phenethyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0269]

[0270] The synthesis method was as in Example 32. It was a white solid with a yield of 45%. 1 H NMR(400MHz,DMSO-d 6)δ10.48(s,1H),7.87(d,J=8.2Hz,2H),7.72(d,J=8.5Hz,2H),7.64(d,J=8.2Hz,2H),7.55–7.47(m,3H),7.45(s,1H),7.22–7.13(m,3H),7.06(d,J=8.2Hz,1H),7.02–6.95(m,2H),4.43(t,J=7.3Hz,2H),3.86(s,2H),3.28(q,J=7.6Hz,2H),3.01(t,J=7.3Hz,2H),2.47(s,3H),1.11(t,J=7.3Hz,3H).MS(ESI),m / z for C 32 H 31 N 3 O 3 S([M+H] + ):Calcd537.68,found 538.6.

[0271] Example 45 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(1-(4-fluorobenzyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0272]

[0273] The synthesis method was the same as that in Example 32. White solid, yield: 26%. 1 H NMR(400MHz,DMSO-d 6 )δ10.48(s,1H),7.85(d,J=8.3Hz,2H),7.73(d,J=8.7Hz,2H),7.65(d,J=8.7Hz,2H),7.62(d,J=8.2Hz,2H),7.57(d,J=8.2Hz,1H),7.28(s,1H),7.11(t,J=8.8Hz,2H),7.07(d,J=8.4Hz,1H),7.04–6.98(m,2H),5.53(s,2H),3.84(s,2H),3.27(q,J=7.2Hz,2H),2.40(s,3H),1.10(t,J=7.3Hz,3H).MS(ESI),m / z for C 31 H 28 FN 3 O 3 S([M+H] + ):Calcd541.64,found 542.3.

[0274] Example 46 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(1-(3-fluorobenzyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0275]

[0276] The synthesis method was the same as that in Example 32, white solid, yield: 29%. 1 H NMR(400MHz,DMSO-d 6 )δ10.48(s,1H),7.85(d,J=8.3Hz,2H),7.73(d,J=8.7Hz,2H),7.69–7.56(m,5H),7.36–7.29(m,1H),7.28(s,1H),7.08(d,J=8.3Hz,2H),6.82(d,J=9.9Hz,1H),6.76(d,J=7.8Hz,1H),5.56(s,2H),3.84(s,2H),3.31–3.23(m,2H),2.40(s,3H),1.10(t,J=7.4Hz,3H).MS(ESI),m / zfor C 31 H 28 FN 3 O 3 S([M+H] + ):Calcd 541.64,found 542.3.

[0277] Example 47 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(1-(2-fluorobenzyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0278]

[0279] The synthesis method was the same as that in Example 32, white solid, yield: 25%. 1 HNMR(400MHz,DMSO-d 6 )δ10.48(s,1H),7.85(d,J=8.2Hz,2H),7.72(d,J=8.6Hz,2H),7.67–7.55(m,5H),7.34–7.25(m,2H),7.20(t,J=8.7Hz,1H),7.11–7.02(m,2H),6.69(t,J=7.6Hz,1H),5.57(s,2H),3.84(s,2H),3.27(q,J=7.2Hz,2H),2.39(s,3H),1.10(t,J=7.3Hz,3H).MS(ESI),m / z forC 31 H28 FN 3 O 3 S([M+H] + ):Calcd 541.64,found 542.3.

[0280] Example 48 N-(4-(1-(2,6-Difluorobenzyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

[0281]

[0282] The synthesis method was the same as that of Example 32, white solid, yield: 35%. 1 HNMR(400MHz,DMSO-d 6 )δ10.49(s,1H),7.86(d,J = 8.2Hz,2H),7.76(d,J = 8.6Hz,2H),7.69(d,J = 8.6Hz,2H),7.64(d,J = 8.1Hz,2H),7.52(d,J = 8.1Hz,1H),7.39–7.28(m,1H),7.18(s,1H),7.07–6.94(m,3H),5.60(s,2H),3.86(s,2H),3.28(q,J = 7.6Hz,2H),2.38(s,3H),1.10(t,J = 7.3Hz,3H).MS(ESI),m / z for C 31 H 27 F 2 N 3 O 3 S([M+H] + ):Calcd 559.63,found 560.3.

[0283] Example 49 N-(4-(1-(4-Cyanobenzyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

[0284]

[0285] The synthesis method was the same as that of Example 32, white solid, yield: 31%. 1 H NMR(400MHz,DMSO-d 6)δ 10.47 (s, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 8.7 Hz, 2H), 7.66–7.55 (m, 5H), 7.26 (s, 1H), 7.14 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 8.3 Hz, 1H), 5.65 (s, 2H), 3.83 (s, 2H), 3.31–3.23 (m, 2H), 2.39 (s, 3H), 1.10 (t, J = 7.3 Hz, 3H). MS(ESI), m / z for C 32 H 28 N 4 O 3 S([M + H] + ): Calcd 548.66, found 549.2.

[0286] Example 50 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(4-(methylsulfonyl)benzyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0287]

[0288] The synthesis method is as in Example 32, white solid, yield: 49%. 1 H NMR (400 MHz, DMSO-d 6 )δ 10.49 (s, 1H), 7.90–7.81 (m, 4H), 7.72 (d, J = 8.6 Hz, 2H), 7.68–7.56 (m, 5H), 7.29–7.18 (m, 3H), 7.08 (d, J = 8.1 Hz, 1H), 5.67 (s, 2H), 3.83 (s, 2H), 3.33–3.23 (m, 2H), 3.17 (s, 3H), 2.39 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H). MS(ESI), m / z for C 32 H 31 N 3 O 5 S 2 ([M - H] - ): Calcd 601.74, found 600.8.

[0289] Example 51 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0290]

[0291] The synthesis method is as in Example 32, white solid, yield: 41%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.46 (s, 1H), 8.49 (d, J = 4.4 Hz, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.79–7.66 (m, 5H), 7.61 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.2 Hz, 1H), 7.31–7.24 (m, 1H), 7.20 (s, 1H), 7.09 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 5.57 (s, 2H), 3.83 (s, 2H), 3.27 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.10 (t, J = 7.3 Hz, 3H). MS (ESI), m / z for C 30 H 28 N 4 O 3 S ([M + H] + ): Calcd 524.64, found 525.4.

[0292] Example 52 N-(4-(1-Benzyl-6-chloro-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-ethylsulfonyl)phenyl)acetamide

[0293]

[0294] The synthesis method is as in Example 32, white solid, yield: 37%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.51 (s, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.77–7.67 (m, 5H), 7.65–7.59 (m, 3H), 7.32–7.19 (m, 4H), 6.97 (d, J = 7.1 Hz, 2H), 5.61 (s, 2H), 3.84 (s, 2H), 3.27 (q, J = 7.3 Hz, 2H), 1.10 (t, J = 7.4 Hz, 3H). MS (ESI), m / z for C 30 H 26 ClN 3 O 3 S ([M + H] + ): Calcd 544.07, found 544.4.

[0295] Example 53 N-(4-(1-Benzyl-5-chloro-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-ethylsulfonyl)phenyl)acetamide

[0296]

[0297] The synthesis method was as in Example 32, white solid, yield: 35%. 1 H NMR(400MHz,DMSO-d 6 )δ10.52(s,1H),7.85(d,J=8.1Hz,2H),7.78–7.67(m,5H),7.62(d,J=8.1Hz,2H),7.51(d,J=8.6Hz,1H),7.31–7.20(m,4H),6.97(d,J=7.0Hz,2H),5.60(s,2H),3.84(s,2H),3.27(q,J=7.2Hz,2H),1.10(t,J=7.3Hz,3H).MS(ESI),m / z for C 30 H 26 ClN 3 O 3 S([M+H] + ):Calcd544.07,found 544.3.HPLC analysis:MeOH(1‰NH 3 ·H 2 O)-H 2 O(75:25),t R =17.64min,96.13%purity.

[0298] Example 54 (S)-2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0299] Step 1. Synthesis of (S)-4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)aniline

[0300]

[0301] Using 3-fluoro-4-nitrotoluene and (S)-1-(4-methylphenyl)ethylamine as raw materials, the synthesis method referred to Steps 1-4 of Example 31. Pale yellow solid, yield: 93%. 1 H NMR(400MHz,DMSO-d 6)δ 7.47 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.1 Hz, 1H), 6.88 (s, 1H), 6.66 (d, J = 8.4 Hz, 2H), 5.80 (q, J = 6.8 Hz, 1H), 5.54 (s, 2H), 2.27 (s, 3H), 2.26 (s, 3H), 1.90 (d, J = 7.1 Hz, 3H).

[0302] Step 2. Synthesis of (S)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0303]

[0304] Dissolve 2-(4-(ethylsulfonyl)phenyl)acetic acid (121.0 mg, 0.53 mmol), HOBT (89.2 mg, 0.66 mmol), EDCI (126.5 mg, 0.66 mmol) and diisopropylethylamine (170.6 mg, 1.32 mmol) in 10 mL of DCM. Stir the reaction mixture for 15 minutes, then add the compound (S)-4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)aniline (150.2 mg, 0.44 mmol), and stir the resulting mixture overnight at room temperature. After completion of the reaction, dilute with water and extract with dichloromethane (50 mL × 3). Combine the organic layers and dry over anhydrous Na 2 SO 4 dry and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (PE:EA = 1:1 v / v) to give the target compound as a white solid (53.4 mg, yield: 22%). 1 H NMR (400 MHz, DMSO-d 6)δ 10.51 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.66–7.58 (m, 4H), 7.53 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 7.8 Hz, 2H), 7.05 (d, J = 7.9 Hz, 2H), 6.99 (d, J = 8.3 Hz, 1H), 6.95 (s, 1H), 5.82–5.72 (m, 1H), 3.85 (s, 2H), 3.31–3.22 (m, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 1.92 (d, J = 7.0 Hz, 3H), 1.10 (t, J = 7.3 Hz, 3H). MS(ESI), m / z for C 33 H 33 N 3 O 3 S([M + H] + ): Calcd 551.71, found 552.8.

[0305] Example 55 Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(pyridin-4-ylmethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0306] Step 1. Synthesis of 5-methyl-2-nitro-N-(pyridin-4-ylmethyl)aniline

[0307]

[0308] Dissolve 3-fluoro-4-nitrotoluene (2 g, 12.9 mmol), 4-pyridinemethanamine (1.68 g, 15.5 mmol) and potassium carbonate (2.68 g, 19.4 mmol) in 20 mL of DMF, and react at 80 °C for 1 h. Monitor the reaction by TLC. After the reaction is completed, cool to room temperature, dilute with water, extract three times with ethyl acetate (50 mL × 3), combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by silica gel column chromatography (PE:EA = 4:1 v / v) to obtain the target compound as a yellow solid (2.2 g, yield: 70%). 1 H NMR (400 MHz, DMSO-d 6 )δ 8.72 (t, J = 6.2 Hz, 1H), 8.51 (d, J = 5.9 Hz, 2H), 7.99 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 5.5 Hz, 2H), 6.65 (s, 1H), 6.52 (dd, J = 8.8, 0.8 Hz, 1H), 4.68 (d, J = 6.4 Hz, 2H), 2.19 (s, 3H).

[0309] Step 2. Synthesis of (6-Methyl-1-(pyridin-4-ylmethyl)-1H-benzo[d]imidazol-2-yl)aniline

[0310]

[0311] Using the intermediate 5-Methyl-2-nitro-N-(pyridin-4-ylmethyl)aniline as the raw material. The synthesis method refers to Steps 2-4 of Example 31. Yellow solid, yield: 69%. 1 H NMR(400MHz,DMSO-d 6 )δ8.49(d,J=6.0Hz,2H),7.53(d,J=8.2Hz,1H),7.32(d,J=8.6Hz,2H),7.15(s,1H),7.04(dd,J=8.2,0.8Hz,1H),6.98(d,J=5.9Hz,2H),6.60(d,J=8.6Hz,2H),5.60–5.47(m,4H),2.37(s,3H).

[0312] Step 3. Synthesis of 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-Methyl-1-(pyridin-4-ylmethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0313]

[0314] Using the intermediate 4-(6-Methyl-1-(pyridin-4-ylmethyl)-1H-benzo[d]imidazol-2-yl)aniline as the raw material, the synthesis method refers to Step 2 of Example 54. White solid, yield: 26%. 1 H NMR(400MHz,DMSO-d 6 )δ10.55(s,1H),8.43(m,2H),7.84(d,J=8.3Hz,2H),7.72(d,J=8.7Hz,2H),7.66–7.57(m,5H),7.24(s,1H),7.09(dd,J=8.2,0.8Hz,1H),6.97–6.93(m,2H),5.58(s,2H),3.84(s,2H),3.26(q,J=7.6Hz,2H),2.39(s,3H),1.10(t,J=7.3Hz,3H).MS(ESI),m / zfor C 30 H 28 N 4 O 3 S([M+H] + ):Calcd 524.64,found 525.4.

[0315] Example 56 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0316]

[0317] The synthesis method is as in Example 54, white solid, yield: 25%. 1 HNMR(400MHz,DMSO-d 6 )δ10.52(s,1H),7.85(d,J=8.2Hz,2H),7.77(d,J=8.6Hz,2H),7.66–7.58(m,4H),7.53(d,J=8.2Hz,1H),7.14(d,J=8.0Hz,2H),7.05(d,J=8.0Hz,2H),6.99(d,J=8.4Hz,1H),6.95(s,1H),5.76(q,J=6.8Hz,2H),3.85(s,2H),3.27(q,J=7.2Hz,2H),2.29(s,3H),2.26(s,3H),1.92(d,J=7.1Hz,3H),1.10(t,J=7.3Hz,3H).MS(ESI),m / z for C 33 H 33 N 3 O 3 S([M+H] + ):Calcd551.71,found 552.6.

[0318] Example 57 (R)-2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0319]

[0320] The synthesis method is as in Example 54, white solid, yield: 18%. 1 HNMR(400MHz,DMSO-d 6)δ10.52(s,1H),7.85(d,J=8.2Hz,2H),7.77(d,J=8.5Hz,2H),7.66–7.58(m,4H),7.53(d,J=8.2Hz,1H),7.14(d,J=8.0Hz,2H),7.05(d,J=8.0Hz,2H),6.99(d,J=8.2Hz,1H),6.95(s,1H),5.76(q,J=6.8Hz,1H),3.85(s,2H),3.27(q,J=7.2Hz,2H),2.29(s,3H),2.26(s,3H),1.92(d,J=7.1Hz,3H),1.10(t,J=7.4Hz,3H).MS(ESI),m / z for C 33 H 33 N 3 O 3 S([M+H] + ):Calcd551.71,found 552.7.

[0321] Example 58 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(1-(4-fluorophenethyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0322]

[0323] The synthesis method is as in Example 54, white solid, yield: 29%. 1 H NMR(400MHz,DMSO-d 6 )δ10.47(s,1H),7.87(d,J=8.4Hz,2H),7.72(d,J=8.7Hz,2H),7.64(d,J=8.4Hz,2H),7.53–7.47(m,3H),7.43(s,1H),7.05(dd,J=8.2,0.8Hz,1H),6.99–6.94(m,4H),4.44(t,J=7.3Hz,2H),3.86(s,2H),3.31–3.23(m,2H),2.98(t,J=7.4Hz,2H),2.46(s,3H),1.11(t,J=7.4Hz,3H).MS(ESI),m / z for C 32 H 30 FN 3 O 3 S([M-H] - ):Calcd 555.67,found554.7.

[0324] Example 59 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0325]

[0326] The synthesis method was the same as that in Example 54. It was a white solid with a yield of 23%. 1 HNMR(400MHz,DMSO-d 6 )δ10.48(s,1H),7.85(d,J = 8.1Hz,2H),7.75–7.54(m,9H),7.26(s,1H),7.18(d,J = 8.1Hz,2H),7.08(d,J = 8.1Hz,1H),5.65(s,2H),3.83(s,2H),3.32–3.22(m,2H),2.39(s,3H),1.09(t,J = 7.3Hz,3H).MS(ESI),m / z for C 32 H 28 F 3 N 3 O 3 S([M-H] - ):Calcd 591.65,found 590.3.

[0327] Example 60 Methyl 4-((2-(4-(2-(4-(ethylsulfonyl)phenyl)acetamido)phenyl)-6-methyl-1H-benzo[d]imidazol-1-yl)methyl)benzoate

[0328]

[0329] The synthesis method was the same as that in Example 54. It was a white solid with a yield of 29%. 1 HNMR(400MHz,DMSO-d 6 )δ10.48(s,1H),7.88(d,J = 8.2Hz,2H),7.84(d,J = 8.3Hz,2H),7.70(d,J = 8.7Hz,2H),7.66–7.56(m,5H),7.24(s,1H),7.12(d,J = 8.2Hz,2H),7.08(dd,J = 8.2,0.4Hz,1H),5.63(s,2H),3.83(s,2H),3.81(s,3H),3.27(q,J = 7.2Hz,2H),2.38(s,3H),1.09(t,J = 7.3Hz,3H).MS(ESI),m / z for C 33 H 31 N3 O 5 S([M+H] + ):Calcd 581.69,found 582.4.

[0330] Example 61 4-((2-(4-(2-(4-(Ethylsulfonyl)phenyl)acetamido)phenyl)-6-methyl-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0331]

[0332] Using the compound of Example 60 as the starting material, the synthesis method was referred to Example 19. A white solid was obtained with a yield of 69%. 1 H NMR(500MHz,DMSO)δ10.78(s,1H),7.87(d,J=8.2Hz,2H),7.84(d,J=8.2Hz,2H),7.81(d,J=8.3Hz,2H),7.74–7.66(m,3H),7.62(d,J=7.9Hz,2H),7.43(s,1H),7.26(d,J=7.9Hz,1H),7.18(d,J=8.0Hz,2H),5.71(s,2H),3.87(s,2H),3.27(q,J=7.5Hz,2H),2.42(s,3H),1.09(t,J=7.3Hz,3H).MS(ESI),m / z for C 32 H 29 N 3 O 5 S([M+H] + ):Calcd567.66,found 568.7.

[0333] Example 62 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(pyridin-3-ylmethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0334]

[0335] The synthesis method was as in Example 54. A white solid was obtained with a yield of 44%. 1 H NMR(400MHz,DMSO-d 6)δ10.51(s,1H),8.46–8.40(t,J=2.8Hz,1H),8.26(s,1H),7.85(d,J=8.1Hz,2H),7.74(d,J=8.5Hz,2H),7.67(d,J=8.6Hz,2H),7.62(d,J=8.1Hz,2H),7.58(d,J=8.3Hz,1H),7.35(s,1H),7.31–7.25(m,2H),7.08(d,J=8.1Hz,1H),5.61(s,2H),3.85(s,2H),3.28(q,J=7.6Hz,2H),2.40(s,3H),1.10(t,J=7.3Hz,3H).MS(ESI),m / z for C 30 H 28 N 4 O 3 S([M+H] + ):Calcd524.64,found 525.4.

[0336] Example 63 (R)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(1-(p-tolyl)ethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0337]

[0338] Synthesized as in Example 54, white solid, yield: 44%. 1 H NMR(400MHz,DMSO-d 6 )δ10.57(s,1H),7.89–7.84(m,3H),7.82(d,J=8.5Hz,2H),7.69(d,J=8.3Hz,2H),7.63(d,J=7.9Hz,2H),7.50(d,J=8.5Hz,1H),7.37(s,1H),7.16(d,J=7.8Hz,2H),7.10(d,J=7.8Hz,2H),5.95–5.83(m,1H),3.86(s,2H),3.31–3.22(m,2H),2.26(s,3H),1.94(d,J=6.9Hz,3H),1.10(t,J=7.3Hz,3H).MS(ESI),m / z for C 33 H 30 F 3 N 3 O 3 S([M-H] - ):Calcd 605.68,found604.4.

[0339] Example 64 (R)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methoxy-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0340]

[0341] The synthesis method is as in Example 54, white solid, yield: 27%. 1 H NMR(400MHz,DMSO-d 6 )δ10.53(s,1H),7.86(d,J=8.2Hz,2H),7.78(d,J=8.6Hz,2H),7.66–7.59(m,4H),7.54(d,J=8.8Hz,1H),7.15(d,J=8.0Hz,2H),7.09(d,J=8.0Hz,2H),6.81(dd,J=8.8,2.2Hz,1H),6.53(d,J=1.9Hz,1H),5.76(q,J=6.8Hz,1H),3.85(s,2H),3.62(s,3H),3.28(q,J=7.4Hz,2H),2.26(s,3H),1.91(d,J=7.1Hz,3H),1.10(t,J=7.3Hz,3H).MS(ESI),m / z for C 33 H 33 N 3 O 4 S([M-H] - ):Calcd 567.70,found 566.4.

[0342] Example 65 (R)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(5-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0343]

[0344] The synthesis method is as in Example 54, white solid, yield: 31%. 1 H NMR(400MHz,DMSO-d 6)δ10.54(s,1H),7.85(d,J=8.3Hz,2H),7.78(d,J=8.6Hz,2H),7.67–7.60(m,4H),7.44(s,1H),7.12(d,J=8.0Hz,2H),7.04(d,J=8.0Hz,2H),6.98(d,J=8.3Hz,1H),6.88(d,J=8.2Hz,1H),5.76(q,J=7.1Hz,1H),3.85(s,2H),3.28(q,J=7.4Hz,2H),2.35(s,3H),2.24(s,3H),1.92(d,J=7.0Hz,3H),1.09(t,J=7.3Hz,3H).MS(ESI),m / z for C 33 H 33 N 3 O 3 S([M-H] - ):Calcd551.71,found 550.4.

[0345] Example 66 (R)-2-(4-(Ethylsulfonyl)phenyl)-N-(4-(5-methoxy-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide (27f)

[0346]

[0347] The synthesis method was as in Example 54, white solid, yield: 25%. 1 H NMR(400MHz,DMSO-d 6 )δ10.53(s,1H),7.85(d,J=7.8Hz,2H),7.78(d,J=8.2Hz,2H),7.69–7.58(m,4H),7.17(s,1H),7.12(d,J=7.5Hz,2H),7.05(d,J=7.5Hz,2H),6.98(d,J=8.9Hz,1H),6.70(d,J=8.8Hz,1H),5.82–5.69(m,1H),3.85(s,2H),3.75(s,3H),3.33–3.22(m,2H),2.25(s,3H),1.91(d,J=6.7Hz,3H),1.10(t,J=7.2Hz,3H).MS(ESI),m / z for C 33 H 33 N 3 O 4 S([M+H] + ):Calcd 567.70,found 568.8.

[0348] Example 67 (R)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(1-(4-fluorophenyl)ethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0349]

[0350] The synthesis method is as in Example 54, white solid, yield: 39%. 1 H NMR(500MHz,DMSO-d 6 )δ10.58(s,1H),7.91–7.84(m,3H),7.82(d,J=7.9Hz,2H),7.69(d,J=8.1Hz,2H),7.63(d,J=7.5Hz,2H),7.51(d,J=8.1Hz,1H),7.35(s,1H),7.30–7.23(m,2H),7.22–7.15(m,2H),5.96–5.96(m,1H),3.86(s,2H),3.32–3.23(m,2H),1.96(d,J=6.5Hz,3H),1.10(t,J=7.1Hz,3H).MS(ESI),m / z for C 32 H 27 F 4 N 3 O 3 S([M-H] - ):Calcd 609.64,found 608.2.HPLC analysis:MeOH-H 2 O(85:15),t R =13.02min,98.08%purity.

[0351] Example 68 (S)-2-(4-(ethylsulfonyl)phenyl)-N-(4-(1-(1-(4-fluorophenyl)ethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0352]

[0353] The synthesis method is as in Example 54, white solid, yield: 28%. 1 H NMR(500MHz,DMSO-d 6)δ10.58(s,1H),7.90–7.83(m,3H),7.82(d,J=8.6Hz,2H),7.69(d,J=8.6Hz,2H),7.63(d,J=8.2Hz,2H),7.51(d,J=8.1Hz,1H),7.35(s,1H),7.29–7.24(m,2H),7.18(t,J=8.8Hz,2H),5.92(q,J=6.8Hz,1H),3.86(s,2H),3.28(q,J=7.4Hz,2H),1.96(d,J=7.1Hz,3H),1.10(t,J=7.3Hz,3H).MS(ESI),m / z for C 32 H 27 F 4 N 3 O 3 S([M-H] - ):Calcd 609.64,found 608.3.

[0354] Example 69 (R)-2-(4-(2-(4-(Ethylsulfonyl)phenyl)acetamido)phenyl)-N-isopropyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazole-6-carboxamide

[0355] Step 1. Synthesis of 3-Fluoro-N-isopropyl-4-nitrobenzamide

[0356]

[0357] Using 3-fluoro-4-nitrobenzoic acid and isopropylammonium as raw materials, the synthesis method refers to Step 5 of Example 31, yellow solid, yield: 95%. 1 HNMR(400MHz,DMSO-d 6 )δ8.59(d,J=7.2Hz,1H),8.25(t,J=8.1Hz,1H),7.97(dd,J=12.1,1.5Hz,1H),7.87(d,J=8.5Hz,1H),4.14–4.02(m,1H),1.18(d,J=6.6Hz,6H).

[0358] Step 2. Synthesis of (R)-2-(4-(2-(4-(Ethylsulfonyl)phenyl)acetamido)phenyl)-N-isopropyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazole-6-carboxamide

[0359]

[0360] Using 3-fluoro-N-isopropyl-4-nitrobenzamide and (R)-1-(4-methylphenyl)ethylamine as raw materials, the synthesis method was referred to Example 53. White solid, yield: 26%. 1 H NMR(400MHz,DMSO-d 6 )δ10.57(s,1H),8.14(d,J=7.8Hz,1H),7.85(d,J=8.3Hz,2H),7.79(d,J=8.7Hz,2H),7.76–7.60(m,7H),7.14(d,J=8.1Hz,2H),7.05(d,J=8.0Hz,2H),5.88–5.80(m,1H),4.10–4.01(m,1H),3.86(s,2H),3.32–3.22(m,2H),2.25(s,3H),1.97(d,J=7.1Hz,3H),1.14(d,J=6.5Hz,6H),1.10(t,J=7.4Hz,3H).MS(ESI),m / z for C 36 H 38 N 4 O 4 S([M-H] - ):Calcd 622.78,found621.0.

[0361] Example 70 (R)-N-cyclopentyl-2-(4-(2-(4-(ethylsulfonyl)phenyl)acetamido)phenyl)-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazole-6-carboxamide

[0362]

[0363] The synthesis method was as in Example 69. White solid, yield: 12%. 1 H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),8.19(d,J=7.0Hz,1H),7.85(d,J=8.3Hz,2H),7.79(d,J=8.3Hz,2H),7.76–7.57(m,7H),7.14(d,J=7.3Hz,2H),7.05(d,J=7.7Hz,2H),5.89–5.78(m,1H),4.23–4.12(m,1H),3.85(s,2H),3.33–3.22(m,2H),2.25(s,3H),1.97(d,J=7.0Hz,3H),1.92–1.79(m,2H),1.75–1.62(m,2H),1.59–1.44(m,4H),1.09(t,J=7.3Hz,3H).MS(ESI),m / z for C 38 H 40 N 4 O 4 S([M+H] + ):Calcd 648.82,found 650.0.

[0364] Example 71 (R)-2-(4-(2-(4-(Ethylsulfonyl)phenyl)acetamido)phenyl)-N-isopropyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide

[0365]

[0366] The synthesis method was as in Example 69, white solid, yield: 29%. 1 HNMR(400MHz,DMSO-d 6 )δ10.57(s,1H),8.18(s,1H),8.14(d,J=6.7Hz,1H),7.86(d,J=7.6Hz,2H),7.81(d,J=7.7Hz,2H),7.68(d,J=7.3Hz,2H),7.63(d,J=7.5Hz,2H),7.57(d,J=7.9Hz,1H),7.17–7.09(m,3H),7.08–7.00(m,2H),5.88–5.74(m,1H),4.16–4.02(m,1H),3.86(s,2H),3.31–3.22(d,J=7.1Hz,2H),2.24(s,3H),1.96(d,J=4.8Hz,3H),1.16(d,J=5.5Hz,6H),1.13–1.07(m,3H).MS(ESI),m / z for C 36 H 38 N 4 O4 S([M+H] + ): Calculated 622.78, found 623.3.

[0367] Example 72 (R)-N-Cyclopentyl-2-(4-(2-(4-(ethylsulfonyl)phenyl)acetamido)phenyl)-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide

[0368]

[0369] The synthesis method was as in Example 69, white solid, yield: 11%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.56 (s, 1H), 8.24–8.15 (m, 2H), 7.85 (d, J = 8.1 Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.16–7.09 (m, 3H), 7.04 (d, J = 7.9 Hz, 2H), 5.86–5.76 (m, 1H), 4.28–4.17 (m, 1H), 3.86 (s, 2H), 3.33–3.23 (m, 2H), 2.24 (s, 3H), 1.96 (d, J = 6.9 Hz, 3H), 1.92–1.80 (m, 2H), 1.76–1.64 (m, 2H), 1.58–1.48 (m, 4H), 1.09 (t, J = 7.3 Hz, 3H). MS (ESI), m / z for C 38 H 40 N 4 O 4 S([M+H] + ): Calculated 648.82, found 649.9.

[0370] Example 73 2-Acetamido-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0371] Step 1. Synthesis of tert-butyl (1-(4-(ethylsulfonyl)phenyl)-2-((4-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)amino)-2-oxoethyl)carbamate

[0372]

[0373] Using (S)-4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)aniline and 2-((tert-butoxycarbonyl)amino)-2-(4-(ethylsulfonyl)phenyl)acetic acid as raw materials, the synthesis method refers to Step 5 of Example 31. White solid, yield: 46%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.62 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.82–7.69 (m, 5H), 7.60 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.2 Hz, 1H), 7.12 (d, J = 7.9 Hz, 2H), 7.04 (d, J = 7.9 Hz, 2H), 6.98 (d, J = 8.3 Hz, 1H), 6.94 (s, 1H), 5.74 (q, J = 7.2 Hz, 1H), 5.52 (d, J = 7.2 Hz, 1H), 3.31–3.20 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 1.90 (d, J = 7.0 Hz, 3H), 1.40 (s, 9H), 1.08 (t, J = 7.3 Hz, 3H).

[0374] Step 2. Synthesis of 2-amino-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0375]

[0376] Dissolve tert-butyl (1-(4-(ethylsulfonyl)phenyl)-2-((4-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)amino)-2-oxoethyl)carbamate (190 mg, 0.28 mmol) in 10 mL of dichloromethane, add dropwise 5 mL of trifluoroacetic acid, and react at room temperature for 3 h. After the reaction is completed, spin off the organic solvent and recrystallize with a mixed solvent of ethyl acetate and petroleum ether. The target product is a white solid (130 mg, yield: 82%). MS (ESI), m / z for C 33 H 34 N 4 O 3 S([M + H] + ): Calcd 566.72, found 567.5.

[0377] Step 3. Synthesis of 2-Acetamido-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0378]

[0379] Dissolve 2-Amino-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide (130 mg, 0.23 mmol) in 10 mL of DCM, then add triethylamine (23.3 mg, 0.23 mmol) and acetic anhydride (23.5 mg, 0.23 mmol), and stir the mixture at room temperature for 3 hours. After the reaction is completed, dilute with water and extract with dichloromethane (50 mL × 3). Combine the organic layers and dry over anhydrous Na 2 SO 4 Dry, and concentrate under reduced pressure. The crude product is separated by silica gel column chromatography (PE:EA = 1:4 v / v) to obtain the target compound as a white solid (86.8 mg, yield: 62%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.74 (s, 1H), 8.89 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.80–7.73 (m, 4H), 7.61 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.2 Hz, 1H), 7.13 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.5 Hz, 1H), 6.94 (s, 1H), 5.82 (d, J = 7.8 Hz, 1H), 5.75 (q, J = 6.9 Hz, 1H), 3.31–3.23 (m, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 1.96 (s, 3H), 1.91 (d, J = 7.1 Hz, 3H), 1.09 (t, J = 7.3 Hz, 3H). MS (ESI), m / z for C 35 H 36 N 4 O 4 S([M+H] + ): Calcd 608.76, found 609.8.

[0380] Isomer 1 (Example 74) and Isomer 2 (Example 75) of Example 73

[0381] Example 73 (2.72 g) was purified by SFC chiral separation (Chiralpak IC, 0.46 cm ID × 15 cm L, 214 nm, hexane / ethanol = 30 / 70 (V / V), 1 mL / min, 35 °C) to obtain the corresponding two isomers: isomer 1 (Example 74) (peak 1, 1.25 g, >98% ee, white solid) and isomer 2 (Example 75) (peak 2, 1.31 g, >98% ee, white solid). Note: Single crystal of the compound has not been obtained yet, and the absolute configuration of the compound cannot be determined.

[0382] Example 74: Isomer 1 (R or S) 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.75 (s, 1H), 8.91 (d, J = 7.7 Hz, 1H), 7.91 (d, J = 7.6 Hz, 2H), 7.79–7.73 (m, 4H), 7.61 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 8.2 Hz, 1H), 7.13 (d, J = 7.6 Hz, 2H), 7.04 (d, J = 7.6 Hz, 2H), 6.99 (d, J = 8.1 Hz, 1H), 6.94 (s, 1H), 5.82 (d, J = 7.7 Hz, 1H), 5.74 (q, J = 6.2 Hz, 1H), 3.28 (q, J = 7.4 Hz, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 1.95 (s, 3H), 1.91 (d, J = 7.0 Hz, 3H), 1.09 (t, J = 7.9 Hz, 3H). MS (ESI), m / z for C 35 H 36 N 4 O 4 S ([M + H] + ): Calcd 608.76, found 609.8.

[0383] Example 75: Isomer 2 (S or R) 1 H NMR (500 MHz, DMSO-d 6)δ10.75(s,1H),8.91(d,J=7.8Hz,1H),7.91(d,J=7.7Hz,2H),7.79–7.74(m,4H),7.61(d,J=8.0Hz,2H),7.53(d,J=8.1Hz,1H),7.13(d,J=7.6Hz,2H),7.04(d,J=7.6Hz,2H),6.99(d,J=8.2Hz,1H),6.94(s,1H),5.82(d,J=7.6Hz,1H),5.74(q,J=6.3Hz,1H),3.28(q,J=7.5Hz,2H),2.29(s,3H),2.25(s,3H),1.95(s,3H),1.91(d,J=7.0Hz,3H),1.09(t,J=7.3Hz,3H).MS(ESI),m / z forC 35 H 36 N 4 O 4 S([M+H] + ):Calcd 608.76,found 609.8.

[0384] Example 76 2-Acetamido-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-pentyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0385]

[0386] The synthesis method was as in Example 73, white solid, yield: 47%. 1 H NMR(400MHz,DMSO-d 6 )δ10.72(s,1H),8.89(d,J=7.6Hz,1H),7.93(d,J=8.1Hz,2H),7.81–7.74(m,4H),7.70(d,J=8.4Hz,2H),7.51(d,J=8.1Hz,1H),7.40(s,1H),7.04(d,J=8.1Hz,1H),5.83(d,J=7.6Hz,1H),4.23(t,J=7.1Hz,2H),3.33–3.24(m,2H),2.46(s,3H),1.96(s,3H),1.70–1.58(m,2H),1.20–1.04(m,7H),0.74(t,J=6.9Hz,3H).MS(ESI),m / z for C 31 H 36 N 4 O 4 S([M+H] +):Calcd 560.71,found 561.8.

[0387] Example 77 2-Acetamido-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-((R)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazo[4,5-b]pyridin-2-yl)phenyl)acetamide

[0388]

[0389] The synthesis method was as in Example 73, white solid, yield: 45%. 1 H NMR(400MHz,DMSO-d 6 )δ10.75(s,1H),8.90(d,J = 7.8Hz,1H),7.91(d,J = 8.4Hz,2H),7.80–7.73(m,4H),7.61(d,J = 8.6Hz,2H),7.53(d,J = 8.2Hz,1H),7.13(d,J = 8.1Hz,2H),7.04(d,J = 7.9Hz,2H),6.98(d,J = 8.6Hz,1H),6.94(s,1H),5.82(d,J = 7.8Hz,1H),5.74(q,J = 6.9Hz,1H),3.28(q,J = 7.4Hz,2H),2.29(s,3H),2.25(s,3H),1.95(s,3H),1.91(d,J = 7.1Hz,3H),1.09(t,J = 7.3Hz,3H).MS(ESI),m / z for C 35 H 36 N 4 O 4 S([M+H] + ):Calcd 608.76,found 609.7.

[0390] Example 78 2-(4-(2-Acetamido-2-(4-(ethylsulfonyl)phenyl)acetamido)phenyl)-N-isopropyl-1-((R)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide

[0391]

[0392] The synthesis method was as in Example 73, white solid, yield: 46%. 1 H NMR(400MHz,DMSO-d 6)δ10.78(s,1H),8.91(d,J=7.7Hz,1H),8.18(s,1H),8.13(d,J=8.1Hz,1H),7.92(d,J=8.4Hz,2H),7.80(d,J=8.6Hz,2H),7.77(d,J=8.3Hz,2H),7.68(d,J=8.5Hz,2H),7.57(d,J=8.8Hz,1H),7.18–7.09(m,3H),7.04(d,J=7.8Hz,2H),5.85–5.75(m,2H),4.15–4.03(m,1H),3.33–3.24(m,2H),2.24(s,3H),1.98–1.91(m,6H),1.15(d,J=6.6Hz,6H),1.09(t,J=7.3Hz,3H).MS(ESI),m / z for C 38 H 41 N 5 O 5 S([M+H] + ):Calcd 679.84,found 680.8.

[0393] Example 79 2-(4-(2-Acetamido-2-(4-(ethylsulfonyl)phenyl)acetamido)phenyl)-N-isopropyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide

[0394]

[0395] The synthesis method is as in Example 73, white solid, yield: 40%. 1 H NMR(400MHz,DMSO-d 6 )δ10.79(s,1H),8.91(d,J=7.8Hz,1H),8.18(s,1H),8.13(d,J=7.7Hz,1H),7.92(d,J=8.4Hz,2H),7.80(d,J=8.6Hz,2H),7.77(d,J=8.4Hz,2H),7.68(d,J=8.6Hz,2H),7.57(dd,J=8.6,1.3Hz,1H),7.17–7.09(m,3H),7.04(d,J=7.7Hz,2H),5.86–5.75(m,2H),4.15–4.03(m,1H),3.33–3.23(m,2H),2.24(s,3H),1.99–1.91(m,6H),1.16(d,J=6.6Hz,6H),1.09(t,J=7.3Hz,3H).MS(ESI),m / z for C38 H 41 N 5 O 5 S([M+Na] + ):Calcd 679.84,found 702.4.

[0396] Example 80 2-Acetamido-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide

[0397] Step 1. Synthesis of (S)-5-methyl-N 1 -(1-(p-tolyl)ethyl)benzene-1,2-diamine

[0398]

[0399] Using 3-fluoro-4-nitrotoluene and (S)-1-(4-methylphenyl)ethylamine as starting materials, the synthesis method refers to Steps 1-2 of Example 31. Yellowish-purple liquid, yield: 90%. 1 H NMR(400MHz,DMSO-d 6 )δ7.24(d,J = 7.5Hz,2H),7.08(d,J = 7.4Hz,2H),6.40(d,J = 7.6Hz,1H),6.13(d,J = 7.4Hz,1H),6.02(s,1H),4.71(d,J = 6.2Hz,1H),4.52–4.29(m,3H),2.24(s,3H),1.94(s,3H),1.41(d,J = 6.5Hz,3H).

[0400] Step 2. Synthesis of (S)-N-(4-methyl-2-((1-(p-tolyl)ethyl)amino)phenyl)-5-nitropyridine

[0401]

[0402] Using (S)-5-methyl-N 1 -(1-(p-tolyl)ethyl)benzene-1,2-diamine and 5-nitro-2-pyridinecarboxylic acid as starting materials, the synthesis method refers to Step 5 of Example 31. Yellow solid, yield: 75%. 1 H NMR(400MHz,DMSO-d 6)δ 10.34 (s, 1H), 9.47 (d, J = 2.4 Hz, 1H), 8.81 (dd, J = 8.6, 2.5 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 7.9 Hz, 2H), 7.21 (d, J = 7.9 Hz, 1H), 7.09 (d, J = 7.8 Hz, 2H), 6.43 (d, J = 8.1 Hz, 1H), 6.32 (s, 1H), 5.30 (d, J = 6.4 Hz, 1H), 4.52–4.42 (m, 1H), 2.25 (s, 3H), 2.09 (s, 3H), 1.38 (d, J = 6.6 Hz, 3H).

[0403] Step 3. Synthesis of (S)-6-methyl-2-(5-nitropyridin-2-yl)-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazole

[0404]

[0405] Dissolve (S)-N-(4-methyl-2-((1-(p-tolyl)ethyl)amino)phenyl)-5-nitropyridine (3.25 g, 8.32 mmol) in 150 mL of glacial acetic acid, and then reflux and stir the solution at 120 °C for 4.5 h. After the reaction is completed, first wash the solution with saturated NaHCO 3 until the acetic acid is completely removed, then extract with ethyl acetate multiple times, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by silica gel column chromatography (PE:EA = 5:1 v / v) to obtain the target compound as a bright yellow solid (2.69 g, yield: 87%). 1 1H NMR (400 MHz, DMSO-d 6 )δ 9.46 (d, J = 2.2 Hz, 1H), 8.76 (dd, J = 8.8, 2.6 Hz, 1H), 8.59 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.32 (q, J = 6.4 Hz, 1H), 7.21 (d, J = 7.9 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 7.07 (d, J = 8.3 Hz, 1H), 6.99 (s, 1H), 2.30 (s, 3H), 2.26 (s, 3H), 1.98 (d, J = 7.1 Hz, 3H).

[0406] Step 4. Synthesis of (S)-6-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-amine

[0407]

[0408] Using (S)-6-methyl-2-(5-nitropyridin-2-yl)-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazole as the raw material, the synthesis method refers to Step 2 of Example 31. White solid, yield: 71%. 1 H NMR (400 MHz, DMSO) δ 8.01–7.95 (m, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.31 (q, J = 7.0 Hz, 1H), 7.18 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 7.08 (dd, J = 8.6, 2.8 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.85 (s, 1H), 5.80 (s, 2H), 2.25 (s, 6H), 1.90 (d, J = 7.1 Hz, 3H).

[0409] Step 5. Synthesis of tert-butyl (1-(4-(ethylsulfonyl)phenyl)-2-((6-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)amino)-2-oxoethyl)carbamate

[0410]

[0411] Using (S)-5-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-2-amine and 2-((tert-butoxycarbonyl)amino)-2-(4-(ethylsulfonyl)phenyl)acetic acid as raw materials, the synthesis method refers to Step 5 of Example 31. White solid, yield: 39%. 1 HNMR (400 MHz, DMSO-d 6 ) δ 10.84 (s, 1H), 8.86 (d, J = 1.5 Hz, 1H), 8.29–8.20 (m, 2H), 7.94–7.85 (m, 3H), 7.78 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 1H), 7.26–7.16 (m, 3H), 7.12 (d, J = 7.8 Hz, 2H), 6.99 (d, J = 8.3 Hz, 1H), 6.92 (s, 1H), 3.33–3.22 (m, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 1.92 (dd, J = 6.9, 2.7 Hz, 3H), 1.40 (s, 9H), 1.09 (t, J = 7.3 Hz, 3H).

[0412] Step 6. Synthesis of 2-amino-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide

[0413]

[0414] Using tert-butyl (1-(4-(ethylsulfonyl)phenyl)-2-((6-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)amino)-2-oxoethyl)carbamate as the raw material, the synthesis method refers to Step 2 of Example 72. White solid, yield: 80%. MS(ESI), m / z for C 32 H 33 N 5 O 3 S([M+H] + ): Calcd 567.71, found 568.8.

[0415] Step 7. Synthesis of 2-acetamido-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide

[0416]

[0417] Using 2-amino-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide as the raw material, the synthesis method refers to Step 3 of Example 72. White solid, yield: 70%. 1 H NMR(400MHz, DMSO-d 6)δ10.96(s,1H),8.95(d,J=7.7Hz,1H),8.87(s,1H),8.31–8.19(m,2H),7.92(d,J=8.3Hz,2H),7.77(d,J=8.3Hz,2H),7.55(d,J=8.2Hz,1H),7.26–7.15(m,3H),7.12(d,J=7.8Hz,2H),6.99(d,J=8.0Hz,1H),6.92(s,1H),5.83(d,J=7.6Hz,1H),3.33–3.23(m,2H),2.27(s,3H),2.25(s,3H),1.96(s,3H),1.92(dd,J=7.0,1.7Hz,3H),1.09(t,J=7.3Hz,3H).MS(ESI),m / z for C 34 H 35 N 5 O 4 S([M+H] + ):Calcd609.75,found 610.7.

[0418] Example 81 2-Acetamido-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-pentyl-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide

[0419]

[0420] Synthesized as in Example 80, white solid, yield: 63%. 1 H NMR(400MHz,DMSO-d 6 )δ10.91(s,1H),8.97–8.88(m,2H),8.27(d,J=8.5Hz,1H),8.18(d,J=7.7Hz,1H),7.93(d,J=7.8Hz,2H),7.78(d,J=7.9Hz,2H),7.55(d,J=8.0Hz,1H),7.42(s,1H),7.07(d,J=7.8Hz,1H),5.82(d,J=7.3Hz,1H),4.81–4.67(m,2H),3.33–3.23(m,2H),2.47(s,3H),1.97(s,3H),1.79–1.67(m,2H),1.31–1.20(m,4H),1.10(t,J=7.2Hz,3H),0.81(t,J=6.4Hz,3H).MS(ESI),m / z for C 30 H 35 N 5 O4 S([M+H] + ): Calcd 561.70, found 562.7.

[0421] Example 82 2-Acetamido-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-((R)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide

[0422]

[0423] The synthesis method is as in Example 80, white solid, yield: 65%. 1 H NMR(400MHz, DMSO-d 6 ) δ 10.96(s, 1H), 8.95(d, J = 7.7Hz, 1H), 8.87(d, J = 1.8Hz, 1H), 8.30–8.21(m, 2H), 7.92(d, J = 8.4Hz, 2H), 7.77(d, J = 8.4Hz, 2H), 7.55(d, J = 8.2Hz, 1H), 7.26–7.16(m, 3H), 7.12(d, J = 8.0Hz, 2H), 6.99(d, J = 8.3Hz, 1H), 6.92(s, 1H), 5.83(d, J = 7.7Hz, 1H), 3.28(q, J = 7.3Hz, 2H), 2.27(s, 3H), 2.25(s, 3H), 1.96(s, 3H), 1.92(dd, J = 7.1, 1.9Hz, 3H), 1.09(t, J = 7.3Hz, 3H). MS(ESI), m / z for C 34 H 35 N 5 O 4 S([M+H] + ): Calcd 609.75, found 610.7.

[0424] Example 83 2-(5-(2-Acetamido-2-(4-(ethylsulfonyl)phenyl)acetamido)pyridin-2-yl)-N-isopropyl-1-((R)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide

[0425]

[0426] The synthesis method is as in Example 80, white solid, yield: 49%. 1 H NMR(400MHz, DMSO-d 6)δ11.00(s,1H),8.95(d,J=7.7Hz,1H),8.92(d,J=2.1Hz,1H),8.34–8.23(m,2H),8.20(d,J=0.8Hz,1H),8.12(d,J=7.7Hz,1H),7.92(d,J=8.4Hz,2H),7.77(d,J=8.4Hz,2H),7.55(dd,J=8.6,1.4Hz,1H),7.25(q,J=7.0Hz,1H),7.18(d,J=8.1Hz,2H),7.15–7.07(m,3H),5.84(d,J=7.7Hz,1H),4.14–4.03(m,1H),3.33–3.24(m,2H),2.24(s,3H),1.99–1.91(m,6H),1.15(d,J=6.5Hz,6H),1.09(t,J=7.3Hz,3H).MS(ESI),m / z for C 37 H 40 N 6 O 5 S([M+Na] + ):Calcd680.82,found 703.3.

[0427] Example 84 2-(5-(2-Acetamido-2-(4-(ethylsulfonyl)phenyl)acetamido)pyridin-2-yl)-N-isopropyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide

[0428]

[0429] Synthesized in the same method as in Example 80, white solid, yield: 33%. 1 H NMR(400MHz,DMSO-d 6)δ11.00(s,1H),8.95(d,J=7.7Hz,1H),8.91(d,J=2.2Hz,1H),8.34–8.24(m,2H),8.20(s,1H),8.12(d,J=7.9Hz,1H),7.92(d,J=8.3Hz,2H),7.77(d,J=8.4Hz,2H),7.55(dd,J=8.7,1.2Hz,1H),7.25(q,J=6.8Hz,1H),7.18(d,J=8.0Hz,2H),7.10(m,3H),5.84(d,J=8.0Hz,1H),4.13–4.02(m,1H),3.32–3.25(m,2H),2.24(s,3H),1.98–1.90(m,6H),1.15(d,J=6.5Hz,6H),1.09(t,J=7.4Hz,3H).MS(ESI),m / z for C 37 H 40 N 6 O 5 S([M-H] - ):Calcd 680.82,found679.5.

[0430] Example 85 N-(4-(1-Benzyl-5,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

[0431]

[0432] Using 1-chloro-4,5-dimethyl-2-nitrobenzene and benzylamine as raw materials, the synthesis method was referred to Example 32. White solid, yield: 43%. 1 H NMR(400MHz,CDCl 3 )δ9.21(s,1H),7.83–7.70(m,2H),7.60–7.50(m,3H),7.49–7.38(m,4H),7.35–7.24(m,3H),7.10–6.96(m,3H),5.36(s,2H),3.77(s,2H),3.14–2.99(m,2H),2.36(s,3H),2.33(s,3H),1.28–1.18(m,3H).MS(ESI),m / z for C 32 H 31 N 3 O 3 S([M+H] + ):Calcd 537.68,found 538.6.

[0433] Example 86 N-(4-(1-Benzyl-5,6-dichloro-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

[0434]

[0435] Using 1,2-dichloro-4-fluoro-5-nitrobenzene and benzylamine as raw materials, the synthesis method refers to Example 32. White solid, yield: 47%. 1 H NMR(400MHz,DMSO-d 6 )δ10.52(s,1H),7.99(s,1H),7.91(s,1H),7.85(d,J=8.2Hz,2H),7.77–7.68(m,4H),7.61(d,J=8.2Hz,2H),7.32–7.20(m,3H),6.96(d,J=7.0Hz,2H),5.63(s,2H),3.84(s,2H),3.27(q,J=7.3Hz,2H),1.10(t,J=7.3Hz,3H).MS(ESI),m / z for C 30 H 25 Cl 2 N 3 O 3 S([M+H] + ):Calcd 578.51,found 578.4.

[0436] Example 87 2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide

[0437]

[0438] Dissolve N-(4-(1-benzyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide (100 mg, 0.19 mmol) in methanol (20 mL), and add Pd-C (100 mg). Stir the reaction mixture under hydrogen protection at room temperature overnight. After the reaction is completed, filter the reaction mixture with silica clay, concentrate the solvent, and then purify it by silica column chromatography (PE:EA = 4:1, v / v) to obtain the target compound as a white solid (65.9 mg, yield: 80%). 1 H NMR(400MHz,DMSO-d 6)δ 10.49 (s, 1H), 8.08 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.01 (dd, J = 8.2, 1.0 Hz, 1H), 3.85 (s, 2H), 3.28 (q, J = 7.4 Hz, 2H), 2.42 (s, 3H), 1.10 (t, J = 7.4 Hz, 3H). MS(ESI), m / z for C 24 H 23 N 3 O 3 S([M + H] + ): Calcd 433.53, found 434.5.

[0439] Test Example 1 In vitro Activity Experiment

[0440] In this test example, the luciferase detection technology (Luciferase) was used to detect the inhibitory effect of the compound of the present invention on the transcriptional activity of RORγ.

[0441] The Luciferase results are shown in Table 1.

[0442] Table 1

[0443]

[0444] Note: "A" refers to IC 50 <0.1 μM, "B" refers to 0.1 μM ≤ IC 50 <1 μM, "C" refers to 1 μM ≤ IC 50 <10 μM, "D" refers to 10 μM ≤ IC 50 <100 μM.

[0445] The activity data in Table 1 indicate that the compounds provided by the present invention can preferably inhibit the transcriptional activity of RORγ.

[0446] Test Example 2 Selectivity Test for RORγ and Its Homologous Proteins

[0447] In this test example, the selectivity of Examples 35, 54, 57, 67, 68 and 74 for RORγ and its homologous proteins in the Luciferase experiment was evaluated.

[0448] Experimental materials: Human renal epithelial cell line 293T cells; DMEM medium containing 10% fetal bovine serum; 96-well transparent plate; Dual-luciferase reporter assay kit; Opti-MEM reagent; Lipo-fectamine 2000 transfection reagent; Recombinant plasmids: Gal4-RORγLBD: 25 ng, RORE_Luc: 25 ng, pG5-luc, luciferase (Renilla); Positive inhibitor: SR2211.

[0449] Experimental method: Human renal epithelial cell line 293T cells were cultured in DMEM medium containing 10% fetal bovine serum. One day before transfection, the cells were seeded into 96-well plates at a density of 1.5x10 4 cells / well. After adherent growth for 24 hours, transient transfection was performed using the method of co-transfection of dual-luciferase reporters. The transfection reagent was Lipo-fectamine 2000, and the transfection reagent and plasmids were diluted with Opti-MEM reagent respectively. Gal4-RORγLBD was 25 ng per well; pG5-luc gene was 25 ng per well; Renilla was 5 ng per well. After co-transfection for 24 hours, compounds at different concentrations were added. After incubation for 24 hours, the luminescence signal was detected using the Luciferase Dual-luciferase Reporter Assay Kit. Each sample had 3 replicates, and the IC 50 value (half inhibitory concentration) was calculated using software.

[0450] Experimental results: The activity data of RORγ and its homologous proteins in the Luciferase experiment for Examples 35, 54, 57, 67, 68 and 74 of the present invention are shown in Table 2.

[0451] Table 2

[0452]

[0453] Experimental results show that: The compounds provided by the present invention have specific selectivity for RORγ. In particular, Examples 35, 54, 57, 67, 68 and 74 show better selectivity for RORγ protein compared to other nuclear receptor proteins.

[0454] Test Example 3: Test on the inhibitory effect on the proliferation of AR-positive prostate cancer cell lines

[0455] This test example evaluated the inhibitory effect of Examples 35, 54, 67, 68 and 74 on the proliferation of AR-positive prostate cancer cell lines.

[0456] Experimental materials: Fluorescence signal detection instrument EnSpire Alpha 2390 multimode microplate reader (produced by Perkin Elmer); 384-well clear-bottom microplate; Cell-Titer GLO luminescent reagent; prostate cancer cell lines LNCaP, C4-2B, and 22Rv1; culture medium and fetal bovine serum required for cell culture. Positive drugs: Enzalutamide, SR2211.

[0457] Experimental method: Seed 500 - 1000 cells per well to be tested with 20 μL of medium in a 384-well clear-bottom microplate (the actual number of cells selected is related to the cell cycle and the volume of the cells themselves). After 12 hours, add 10 μL of culture medium containing the compound (compound concentration ranges from 5 nM to 100 nM) to each well. After incubating with the compound for 72 - 96 hours, add Cell-Titer GLO reagent to each well, shake the plate for 20 min to lyse the cells. After incubating for 10 min, centrifuge for 1 min and measure the luminescence 384 signal value. Use GraphPad Prism software to fit the inhibition curve and calculate the IC 50 .

[0458] Experimental results: The anti-proliferative activities of Examples 35, 54, 67, 68, and 74 of the present invention against AR-positive prostate cancer cell lines are shown in Table 3.

[0459] Table 3

[0460]

[0461] As can be seen from the results in Table 4, the IC 50 value of the compound provided by the present invention can be much smaller than the IC 50 value of the currently marketed drug Enzalutamide, and has a better effect of inhibiting the proliferation of prostate cancer cells.

[0462] Test Example 4 Pharmacokinetic evaluation

[0463] This test example conducts pharmacokinetic evaluation on Examples 67 and 68.

[0464] Experimental materials: Pharmacokinetic analysis is performed by Medicilon Corporation in Shanghai. Sprague-Dawley (SD) rats are provided by Shanghai Super-B&K laboratory animal Corp., Ltd.

[0465] Experimental method: The compound was dissolved in 5% DMA, 10% Solutol and 85% Saline to prepare a stock solution. The stock solution was orally administered to 3 SD rats at a dose of 25 mg / kg, and intravenously administered to 3 SD rats at a single dose of 5 mg / kg. Blood was collected from the jugular vein before oral administration and at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after oral administration. Blood was collected from the jugular vein before intravenous injection and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after intravenous injection. Approximately 200 μL of blood samples were collected into heparinized tubes, and then immediately centrifuged at 8000 revolutions per minute for 6 minutes. The obtained plasma was stored at -80 °C until analysis.

[0466] Experimental results: The pharmacokinetic data of Examples 67 and 68 are shown in Table 4 as follows:

[0467] Table 4

[0468]

[0469] Note: —— represents that the data was not measured.

[0470] Experimental results show that: The compounds provided by the present invention have good pharmacokinetic properties.

[0471] Test Example 5 Pharmacodynamic study in 22Rv1 xenograft model mice

[0472] Experimental purpose: For the xenograft mouse experiment, this experiment was used to verify the inhibitory effect of the compounds of the present invention on tumors in vivo.

[0473] Experimental method: Three-week-old male mice (strain: NOD / MrkBomTac-Prkdc scid ) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. and used for the establishment of xenograft tumors. 22Rv1 tumor cells were subcutaneously inoculated on one side of the lower abdomen of each mouse, and 3×10 6 cells were injected into each mouse. The cells were suspended in 100 μL of PBS and Matrigel (ratio 1:1). When the tumor volume reached about 100 mm 3 or so, the mice were randomly grouped (n = 6 - 7 per group), and then the mice were administered by oral gavage. Example 68 was dissolved in a dosing vehicle of 15% polyoxyethylene ether (35) castor oil (Cremophor EL), Calbiochem, 82.5% PBS and 2.5% dimethyl sulfoxide (DMSO). The administration was continued for three weeks, five days a week. The length (L) and width (W) of the tumor mass were monitored by calipers, and the volume was expressed in mm 3 and calculated using the following formula: V = π / 6 × (L × W2 )。The tumor growth inhibition (TGI) was calculated using the following formula: TGI = [1 - (T - T 0 ) / (C - C 0 )] × 100, where T is the average tumor volume on a specific experimental day, and T 0 is the average tumor volume at the beginning of treatment; similarly, C and C 0 are the average tumor volumes of the blank group on a specific experimental day and at the beginning of treatment, respectively.

[0474] Test Example 5 was detected by an experiment using a mouse transplanted tumor model. A mouse model xenografted with 22Rv1 prostate cancer cells was selected. Through oral administration of Example 68 (dosage: 10 mg / kg or 40 mg / kg), it was administered five times a week for 3 weeks, and the changes in the tumor volume in the mice were observed. The data were expressed as the average tumor volume ± standard deviation of the animals in each treatment group (n = 6 - 7 per group).

[0475] The results of the inhibitory effect of Example 68 on tumors in the 22Rv1 mouse transplanted tumor model are shown in Figure 1 and 2 : Figure 1 It was shown that Example 68 could significantly inhibit the growth of tumors in mice at a dosage of 10 mg / kg (TGI = 83%). At a dosage of 40 mg / kg, it could not only significantly inhibit the growth of tumors in mice, but also cause the tumors to completely regress for a long and continuous time (TGI = 109%). In addition, Figure 2 it was shown that at all dosages of Example 68, there were no obvious changes in the body weight of the mice and their behavior was normal. These results indicate that Example 68 has a significant effect of inhibiting the growth of tumors in vivo in the 22Rv1 mouse transplanted tumor model and has no obvious toxic effects.

[0476] These compounds inhibit the downstream signaling pathway by effectively binding to and inhibiting the transcription of the RORγ receptor protein, thereby inhibiting tumor growth and improving inflammation and other effects. Example 68 specifically demonstrated its effect of inhibiting the growth of prostate tumors in vivo. According to the existing reported evidence, it also indicates that such compounds have the potential to be used in the treatment of diseases such as cancer, cell proliferative disorders, inflammatory diseases, autoimmune diseases, sepsis, and viral infections.

[0477] The applicant declares that the present invention uses the above examples to illustrate the benzofive-membered nitrogen-containing heterocyclic compounds of the present invention and their applications, but the present invention is not limited to the above examples, that is, it does not mean that the present invention must rely on the above examples to be implemented. Those skilled in the art should understand that any improvement to the present invention, the equivalent replacement of each raw material of the products of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the protection scope and the disclosure scope of the present invention.

Claims

1. A benzofive-membered nitrogen heterocyclic compound, characterized in that, the benzofive-membered nitrogen heterocyclic compound is any one of the following compounds: 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(4-methylphenethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide N-(4-(1-Butyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-pentyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(1-isopropyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(1-isopentyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide N-(4-(1-Benzyl-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(4-methylbenzyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-phenethyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(1-(4-fluorobenzyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(1-(3-fluorobenzyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(1-(2-fluorobenzyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide N-(4-(1-(2,6-difluorobenzyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide N-(4-(1-(4-cyanobenzyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide N-(4-(1-Benzyl-6-chloro-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-ethylsulfonyl)phenyl)acetamide N-(4-(1-Benzyl-5-chloro-1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-ethylsulfonyl)phenyl)acetamide (S)-2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(pyridin-4-ylmethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide (R)-2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(1-(4-fluorophenethyl)-6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide 2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-(pyridin-3-ylmethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide (R)-2-(4-(Ethylsulfonyl)phenyl)-N-(4-(1-(1-(p-tolyl)ethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide (R)-2-(4-(Ethylsulfonyl)phenyl)-N-(4-(6-methoxy-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide (R)-2-(4-(Ethylsulfonyl)phenyl)-N-(4-(1-(1-(4-fluorophenyl)ethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide (S)-2-(4-(Ethylsulfonyl)phenyl)-N-(4-(1-(1-(4-fluorophenyl)ethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide (R)-2-(4-(2-(4-(Ethylsulfonyl)phenyl)acetamido)phenyl)-N-isopropyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazole-6-carboxamide (R)-N-Cyclopentyl-2-(4-(2-(4-(Ethylsulfonyl)phenyl)acetamido)phenyl)-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazole-6-carboxamide (R)-2-(4-(2-(4-(Ethylsulfonyl)phenyl)acetamido)phenyl)-N-isopropyl-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide (R)-N-Cyclopentyl-2-(4-(2-(4-(ethylsulfonyl)phenyl)acetamido)phenyl)-1-(1-(p-tolyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide 2-Acetamido-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide 2-Acetamido-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-pentyl-1H-benzo[d]imidazol-2-yl)phenyl)acetamide 2-Acetamido-2-(4-(ethylsulfonyl)phenyl)-N-(4-(6-methyl-1-((R)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide 2-Acetamido-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-((S)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide 2-Acetamido-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-pentyl-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide 2-Acetamido-2-(4-(ethylsulfonyl)phenyl)-N-(6-(6-methyl-1-((R)-1-(p-tolyl)ethyl)-1H-benzo[d]imidazol-2-yl)pyridin-3-yl)acetamide.

2. A pharmaceutically acceptable salt or racemate of the benzopentazole compound according to claim 1.

3. Use of the benzopentazole compound according to claim 1 or the pharmaceutically acceptable salt or racemate according to claim 2 in the preparation of an RORγ receptor inhibitor.

4. According to the use of claim 3, wherein, the RORγ receptor inhibitor is used for the preparation of a medicament for treating cancer, cell proliferative disorder diseases, inflammatory diseases, autoimmune diseases, sepsis, viral infections, and neurodegenerative diseases.

5. According to the use of claim 3, wherein, the RORγ receptor inhibitor is used for the preparation of a medicament for treating cancer.

6. According to the use of claim 3, wherein, the RORγ receptor inhibitor is used for the preparation of a medicament for treating prostate cancer.

7. A pharmaceutical composition, wherein, the active ingredient of the pharmaceutical composition comprises the benzopentazole compound according to claim 1 or the pharmaceutically acceptable salt or racemate according to claim 2.

8. Use of the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating, preventing or improving inflammation, autoimmune diseases, cell proliferative disorder diseases, sepsis, cancer, viral infections or neurodegenerative diseases.

9. According to the use of the pharmaceutical composition of claim 8, wherein, the cancer includes prostate cancer.

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